Introduction
Sarcopenia is a skeletal muscle disorder characterized by the progressive loss of
skeletal muscle mass and muscle strength or function as defined in 2010 by the
European Working Group on Sarcopenia in Older People (EWGSOP) and updated in 2019
[1]
[2]. Currently,
there is no globally accepted threshold for sarcopenia, and various research groups
have differing definitions [1]
[2]
[3]
[4]; the
Asian Working Group for Sarcopenia (AWGS), for example, defined cut-offs and gave
the definition for the Asian population [3],
emphasizing that individual ethnic groups require different diagnostic criteria
[3]
[5]
[6]. Secondary data analysis of general population
studies suggests that the global prevalence of sarcopenia in those over 60 is around
10% [7], while an estimated 50% of
those aged 80 or over are sarcopenic [8]. This
phenomenon constitutes an ever-increasing health burden on our society as the
consequences of sarcopenia include an increased risk of mortality, falls and
fractures [9]. One third of patients over 65
experience falls in the community, while this figure rises to half of patients over
65 in long term care [10]. The risk factors for
sarcopenia include older age, immobility or inactivity from a sedentary lifestyle,
and following a poor diet resulting in malnutrition [11]. Diagnosis of sarcopenia is based on low muscle mass, strength and
performance as evidenced by several non-invasive and invasive procedures such as
anthropometric measurements, muscle strength and performance tests, diagnostic tools
such as computed tomography, magnetic resonance imaging, dual x-ray absorptiometry,
bio-electrical impedance analysis, ultrasound, muscle biopsies, biochemical markers,
electromyography and longitudinal monitoring [12]
[13].
To promote healthy aging, multiple pharmacological approaches to treat sarcopenia
have been developed and discussed in detail elsewhere. In brief, such experimental
interventions include anabolic hormones, selective androgen receptor modulators,
exercise mimetics, myostatin inhibitors, angiotensin converting enzyme inhibitors
and several natural compounds [14]
[15]. Besides, published guidelines [16] recommend physical exercise as the first approach
to treating sarcopenia, as shown in [Fig. 1]. There
is also compelling evidence on the benefits of resistance exercise training on
muscle mass and strength [17], endurance training to
improve muscle performance [18] and balance exercises
[19] to improve postural instability, which is
common in sarcopenic patients. Exercise is usually followed by a protein-rich diet
or protein supplementation, including whey or leucine [16]
[20]
[21],
as there is evidence to suggest that protein supplementation improves physical
performance in older people [22], and ideally, this
should be combined with exercise [3]
[16]. Physical exercise combined with nutritional
supplementation appears to be more effective in improving body composition and
physical function than physical exercise per se, as Daly et al. [23] found that a protein-enriched diet, together with
resistance training, increased lean muscle mass; however, there is also evidence to
contradict this in that there is no significant improvement [24]. Although the recommended daily protein intake for adults is
0.8 g/kg of body mass, this target is met by only an estimated
40% of adults [25]
[26]. However, consumption of at least 20 g of protein per meal by
older adults results in significant muscle growth [27].
Fig. 1 Current treatment recommendations for sarcopenia. The
first-line treatment option is exercise (which includes resistance and
endurance training, and balance exercises). The second-line treatment is
protein supplementation or for patients to follow a high-protein (which
includes whey protein). Exercise therapy can be combined with protein
supplementation to treat sarcopenia. Vitamin D is not currently recommended
as a treatment option due to insufficient evidence on the effectiveness of
supplementation of improving sarcopenia criteria in non-vitamin D deficient
patients. This figure was created based on evidence from articles [16]
[17]
[18]
[19]
[20]
[21]
[22]
[23].
In general, there have been mixed findings around the benefits of dietary
supplementation on muscle metabolism. High doses of the amino acids arginine and
lysine are thought to slightly increase the levels of circulating growth hormone to
act on muscle metabolism, while supplementing B-hydroxy-B-methylbutyrate (a
metabolite of leucine) is thought to decrease muscle proteolysis and increase
cholesterol synthesis [28]. However, beyond
protein-rich diets, another nutritional supplement of increasing interest for
sarcopenia is vitamin D [29]
[30]
[31]. Vitamin D is a fat-soluble vitamin
either synthesized in the skin under sunlight exposure by converting
7-dehydrocholesterol into pre-vitamin D3 and in turn into cholecalciferol or
naturally present in certain foods such as dairy products, fish and vegetables [32]. In addition to regulating
Ca2+concentration in the blood, vitamin D plays a regulatory role
in skeletal muscle function and metabolism affecting protein synthesis [33], myogenesis [34],
mitochondrial oxygen consumption [35] and myocyte
differentiation and proliferation [36]. A systematic
review [37] of 16 randomized control trials (mentioned
as trials in the rest of the article) provided evidence of a beneficial effect of
vitamin D supplementation in the older adults in terms of muscle strength and
function. Conversely, an increasing number of studies show a lack of beneficial
effects on muscle strength and function in the older adults [38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46].
Beyond this conflicting data, it has been reported that lean mass is improved in
sarcopenic participants when leucine supplementation is co-administered with vitamin
D [21]. However, vitamin D plus protein
supplementation increased muscle strength in sarcopenic patients but found no strong
evidence for an increase in muscle mass and performance [47].
While there appears to be abundant evidence linking vitamin D deficiency with
sarcopenia in the older adults [48]
[49]
[50]
[51]
[52], there is
conflicting evidence regarding the use of vitamin D as a nutritional supplement for
the treatment and prevention of sarcopenia in non-vitamin D deficient individuals.
It has been suggested that the discrepancies in results between studies showing
positive effects from vitamin D supplementation on muscle strength, mass, and
performance against studies showing no positive effects may be due to the duration
of the interventions, the state of vitamin D insufficiency in the patients, or the
amount and type of vitamin D used [31]. Therefore, the
evidence for vitamin D supplementation as a nutritional therapy is rather
inconsistent and requires further investigation towards a potential treatment for
sarcopenia in patients without vitamin D deficiency [16]
[31].
Previous trials of sarcopenic patients have investigated the effect of vitamin D when
co-administered with other supplements, including proteins, vitamins, and fatty
acids, and exercise, but no trials or papers have investigated the effect of vitamin
D alone on non-vitamin D deficient sarcopenic patients, and thus examined how
vitamin D might be used in the prevention of sarcopenia. Therefore, the aim of this
review is A) to discuss the clinical evidence of vitamin D supplementation both i)
alone and ii) combined with other strategies in the prevention of sarcopenia in
non-sarcopenic individuals and B) critically discuss the clinical evidence on the
effect of vitamin D combined with other strategies on muscle strength, mass and
function in sarcopenic individuals without vitamin D deficiency.
Materials and Methods
Trial characteristics and interventions
An electronic literature search on the PubMed database was conducted and included
trials published from 2011 onwards until December 2022 complying with the
ethical standards of the Journal [53]. A
combination of the following keywords ‘sarcopenia’,
‘vitamin D’, ‘elderly’, ‘older
adults’ and ‘trial’ were used. Initially, 591 studies
were identified ([Fig. 2]). Upon screening the
titles and abstracts, this was narrowed down to 69 randomized control trials.
Non-clinical trial papers were not included in this review. After reading the
full text, 18 trials were included in this review. Trials were excluded if there
were no quantitative data; if the studies were open label (i. e.
information was not blinded to participants); if both placebo and intervention
groups were given vitamin D supplementation; if participants were not healthy or
sarcopenia was secondary to another disease (such as COPD); if the sarcopenia
criteria were not assessed; and if the patients were vitamin D deficient, since
the link between vitamin D deficiency and sarcopenia is well established [48]
[49]
[50]
[51]
[52].
Fig. 2 Flow chart detailing the screening process for the trials
included in this review. Records were excluded if they did not fit the
inclusion criteria. N=591 records were identified through PubMed
search, by screening the title and abstract. N=522 records were
excluded at this stage. The full text was assessed in N=69
articles, at which point N=52 records were excluded. Eighteen
studies have been included in this review that fit the inclusion
criteria.
Of note, the studies by Hajj et al. [54] and
Takeuchi et al. [55] were included based on
limited evidence on the effect of vitamin D alone, despite the authors studying
both vitamin D deficient and non-deficient individuals. Similarly, the study by
Verschueren et al. [56] was also included despite
the intervention and placebo group both receiving vitamin D supplementation,
because these studies [54]
[56] were two out of the only three trials [54]
[56]
[57] conducted to assess vitamin D supplementation alone on
non-sarcopenic individuals. In this review, we followed the EWGSOP criteria of
sarcopenia: muscle strength (assessed in terms of handgrip and knee extensor
strength), muscle mass (lean mass/appendicular/skeletal muscle
mass index), and function (i. e. chair stand, gait speed, timed
up-and-go (TUG), short physical performance battery test (SPPB) which consists
of three tests: standing balance, gait speed, and 5-times sit-to-stand) [1]
[2]. Other measures
of physical function included 4-, 5-, or 6-minute walking tests. Although these
tests are not standard measures of physical function according to the EGSWOP
criteria, we included them in this review based on the limited data on physical
function.
The literature research identified 18 trials in total, and of these three trials
investigated the effects on vitamin D supplementation alone on non-sarcopenic
individuals [54]
[56]
[57]
[58]. In these trials, the vitamin D intervention was generally
administered at higher doses when given alone than when administered as a
combined supplement, ranging from 1,000 IU/day for a period of 9 months
to 10,000 IU three times per week for a period of 6 months [57]
[58]. In the
non-sarcopenic combined supplementation group, participants in two trials
received the conventional dose of 800 IU/day for 6 weeks and 12 weeks
[59]
[60], while
in one trial 1,000 IU/day was administered for 12 weeks [61]. In sarcopenic individuals, 12 trials [55]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72] were
identified for vitamin D combined supplementation therapy. Here, vitamin D was
administered as a combined supplement for 12 weeks (or 3 months) at doses of 100
IU [69], 130 IU [72], 250 IU [65], 800 IU [62]
[63]
[71] and 1,000 IU [67]; 500 IU over 8 weeks [55]; 702 IU for 6
months [64]; 800 IU for 4–8 weeks (until
hospital discharge) [68]; and 800 IU over 13 weeks
[70]. We denote when trials used additional
supplements as part of their interventions. In non-sarcopenic participants,
vitamin D was co-supplemented with: leucine [59]
[60], whey, soy and casein [60], and amino acids [61]. In sarcopenic individuals, vitamin D was co-supplemented with:
whey [63]
[64]
[65]
[67]
[68]
[69]
[70]
[71]; leucine
[62]
[63]
[68]
[70];
branched-chain amino acids [55]
[68]; omega-3 fatty acids [67]
[72]; casein [67]; creatine [67];
medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs) [62]; B-methylbutyrate [72]; and vitamin E [64]. Of the six
non-sarcopenic trials analyzed, only one included exercise as an additional
therapy, consisting of whole-body vibration training three times per week [56]. Six out of twelve trials for the sarcopenic
participants included exercise therapy, which were resistance training [65]
[67]
[68]
[69]
[71], balance training [68]
[69], aerobic exercise [65] and combined resistance/aerobic group
training [72].
The non-sarcopenic group had a larger mean age range than the sarcopenic group of
studies, as two trials focused on younger adults (mean age 58.4 years [60] and 58.8 years [57]. The other study population ages were 68 years [61], 71 years [59],
73.3 years [54], while the upper age limit was
79.6 in the study by Verschueren et al. [56]. The
sarcopenic study ages were 70.0 (in the subgroup that received only the
nutritional supplement) [65], 71.0 [66], 73.2 [64], 74.8
[72], 77.4 [67],
77.7 [63]
[70], 79.9
[55], 80.3 [69],
81.0 [68], 84.2 [71], and 86.6 [62]. Of note, in the study
by Nilsson et al. [67], sarcopenia participants
were randomized into groups along with non-sarcopenic participants, although
this trial also included a sarcopenia-subgroup analysis of muscle strength,
muscle mass, and physical function. However, the proportion of sarcopenic
participants in the intervention and placebo groups compared to non-sarcopenic
participants is unclear. Only a small number of sarcopenic participants were
included in the trial, therefore increasing the risk of type 2 error so the
results should be interpreted with caution. The trial characteristics are
summarized in [Tables 1]
[2]. Changes in muscle strength, muscle mass and function have been
calculated by the authors to the best of their ability as percentual changes
against the baseline or placebo values as appropriate.
Table 1 The effects of vitamin D supplementation on the
sarcopenia criteria in non-sarcopenic patients.
|
Author, year
|
Population
|
Mean Age (Years)
|
Sample Size
|
Intervention
|
Exercise
|
Duration
|
Sarcopenia Indices
|
Hand grip strength
|
Lean mass
|
Physical function
|
|
HS/MS
|
LM
|
PF
|
|
Cangussu et al., 2015[57]
|
Postmeno-pausal women
|
58.8±6.6/59.3±6.7
|
160, 20 discont.
|
1000 IU/day vit D
|
No exercise
|
9 months
|
HS
|
ALM, TLM
|
CRT
|
Not altered significantly
|
Not altered significantly
|
Improved CRT:+25.3%
|
|
Chanet et al., 2017[59]
|
Elderly men
|
71±4
|
24
|
800 IU/day vit D+21 g
leucine-enriched whey+9 g
carbs+3 g fat
|
No exercise
|
6 weeks
|
HS
|
SMMI
|
SPPB
|
Not altered significantly
|
Improved ALM:+2.4%
|
Not altered significantly
|
|
Hajj et al., 2018[54]
|
Pre-sarcopenic elderly
|
73.3± 2.05
|
128
|
10000 IU vit D 3x/wk
|
No exercise
|
6 months
|
HS
|
ASMM
|
Not determined
|
Improved HS:+3.2%
|
Improved ASMM 3.1%
|
Not measured
|
|
Kang et al., 2020[60]
|
Late middle-aged adults
|
58.38±5.72
|
120
|
800 IU/day vit D+20 g protein
(50% casein, 40% whey, 10% soy,
3000 mg leucine)
|
No exercise
|
12 weeks
|
HS, FMS
|
ASMM, ALM
|
SPPB
|
Not altered significantly
|
Improved ALM:+1.2%,
|
Not altered significantly
|
|
Negro et al., 2019[61]
|
Elderly adults
|
68±4.6
|
38
|
1000 IU 2x/d vit D+Essential Amino Acids
(EAA)-based multi-ingredient nutritional supplement
– 5000 mg EAA, 1500 mg creatine,
muscle restore complex
|
No exercise
|
12 weeks
|
MVC
|
ALM
|
Not determined
|
Improved MVC:+5.7%
|
Improved ALM:+1.7%
|
Not measured
|
|
Verschueren et al., 2011[56]
|
Postmeno-pausal women
|
79.6
|
113
|
880 IU/day vit D (conventional), or 1600
IU/day vit D (high dose)
|
WBVT 3/week or a no-training group
|
6 months
|
Isometric and dynamic strength (Nm) – isokinetic
dynamometry
|
Muscle mass (cm)
|
Not deter-mined
|
Improved
|
Not altered significant-ly
|
Not measured
|
|
DKE:+6.4% WBVT DMS:
|
|
+7.9%
|
|
1600 IU=+8.1%
|
|
880 IU=6.3%
|
Abbreviations: ALM – appendicular lean mass; DMS –
dynamic muscle strength; CRT – chair rising test; DKE –
dynamic knee extensor; FMS: femoral muscle strength; HD –
handgrip dynamometry; HS: handgrip strength; MS – muscle mass;
MVC – maximal voluntary contraction; SMM – appendicular
skeletal muscle mass; SMMI – skeletal muscle mass index; SPPB
– short physical performance battery test; TLM – total
lean mass; WBVT – whole body vibration training.
Table 2 The effects of vitamin D supplementation on the
sarcopenia criteria in sarcopenic patients.
|
Author, year
|
Population
|
Mean Age (Years)
|
Sample Size
|
Intervention
|
Exercise
|
Duration
|
Sarcopenia Indices
|
Hand grip strength
|
Lean mass
|
Physical function
|
|
HS/MS
|
LM
|
PF
|
|
Abe et al., 2016[62]
|
Elderly adults
|
86.6±4.8
|
38
|
Arm 1–800 IU vit D+1.2g
L-leucine+6 g MCTs
|
No exercise
|
3 months
|
HS
|
AC, CC
|
GS
|
Improved
|
Not altered significantly
|
Improved Arm 1 GS:+12.5%
|
|
Arm 2–800 IU vit D+1.2g
L-leucine+6 g LCTS
|
Arm 1 right HS:+13.1%
|
|
Bauer et al., 2015 [63]
|
Elderly adults
|
77.7
|
380
|
800 IU vit D+3 g leucine enriched
20 g whey protein
|
No exercise
|
13 weeks
|
HS
|
AMM
|
SPPB – GS, CS, balance
|
Not altered significantly
|
Improved AMM: ~+1.3%
|
Not altered significantly
|
|
Bo et al., 2019 [64]
|
Elderly adults
|
73.23±6.52
|
60
|
702 IU vit D+22 g whey protein+vit E
2x daily
|
No exercise
|
6 months
|
HS
|
RSMM, BIA AMM (Kg)
|
GS, CS, TUG
|
Improved
|
Not altered significantly
|
Not altered significantly
|
|
HS:+9.8%
|
|
Li et al., 2020 [65]
|
Elderly adults
|
Nutr: 70.04 Ex+nutr
|
|
250 IU vitamin D, 10 g whey
protein+300 mg EPA+200 mg
DHA
|
Aerobic & resistance exercise
|
12 weeks
|
Hand grip strength
|
ASMM, RSMI
|
GS
|
Improved
|
Improved:
|
Not measured
|
|
3 study arms: Nutr; Ex; Nutr+Ex
|
HS:Nutr+19.9%
|
ASM: Nutr:+4.7%
|
|
Ex+14.3%
|
Ex:+2.2%
|
|
Nutr+Ex+15.0%
|
Nutr+Ex:+3.5%
|
|
Nasimi et al., 2021 [66]
|
Elderly adults
|
71.0 (69.0, 73.5)
|
66
|
1000 IU/d vit D+3 g beta-Hydroxy
beta-Methyl Butyrate +500 mg vit C
(fortified yoghurt)
|
No exercise
|
12 weeks
|
HS
|
LBM, ALM, SMMI
|
GS
|
Improved
|
No significant change
|
Improved GS:+10.7%
|
|
HS:+30.5%
|
|
Nilsson et al., 2020 [67]
|
Elderly men
|
77.3±2.8
|
45
|
1000 IU/d vit+24 g whey
protein+16 g casein+3 g
creatine+omega-3 fish oil
|
3 d/wk whole body elastic band RE
|
12 weeks
|
LP, HS, IKE (kg)
|
TLM (kg), ASM (kg)
|
GS, STS, TUG, 4 m walk, 4 step stair climb, SPPB
|
Improved
|
Improved
|
Improved
|
|
(M5)
|
HBRE
|
M5 group LP: 14.8%,
|
Sarcopenia all:
|
STS: -8.3%
|
|
HS: 7.8%,
|
TLM: 3.3%
|
6 meter walk test: 7.4%
|
|
Sarcopenia: not significantly improved
|
ASM:+4.3%
|
4 step chair climb: -20.3%
|
|
M5: TLM 3.4%
|
|
ALM: 4.1%
|
|
Rondanelli et al., 2016 [69]
|
Elderly adults
|
80.3 (80.77±6.29)
|
130
|
100 IU/d vit D+whey protein
22 g/d+10.9 g essential
amino acids (including 4 g leucine)
|
Resistance and balance exercise
|
12 weeks
|
HS (kg)
|
RSMM
|
Not measured
|
Improved
|
Improved – RSMM=3.2%
|
Not measured
|
|
HS:+19.2%
|
|
Rondanelli et al., 2020 [68]
|
Elderly adults
|
81±6
|
140
|
800 IU vit D 2x/d+20 g whey
protein-based supp enriched with leucine
|
Exercise program – balance and resistance training,
20 min 5x/wk
|
4–8 weeks
|
HS
|
AMM (g), SMMI (kg/m2)
|
GS, CS, TUG, SPPBNot measured
|
Improved
|
Improved
|
Improved
GS: + 0.061 m/s/month
|
|
HS:+21.9%
|
AMM:+6.2%
|
CS:+28.2%
|
|
SMMI:+6.4%
|
TUG:+12.4%, SPPB:+65.0%
|
|
Takeuchi et al., 2019 [55]
|
Elderly adults
|
78.8 ± 5.1
|
68
|
500 IU vit D+10 g BCAA 125ug
|
No exercise
|
8 weeks
|
HS
|
AC, (cm), CC (cm)
|
Improved
|
Improved:
|
Not measured
|
|
HS:+40.5%
|
AC:+5.8%
|
|
|
CC:+3.8%
|
|
Verlaan et al., 2018 [70]
|
Elderly adults
|
77.7
|
380
|
800 IU vit D+20 g whey, 3 g leucine,
|
No exercise
|
13 weeks
|
HS
|
AMM kg,
|
SPPB, GS, CS
|
Not measured
|
Improved – AMM:
|
Not altered significantly
|
|
Yamada et al., 2019 [71]
|
Elderly adults
|
84.2±5.5
|
112
|
800 IU vit D+10 g whey protein
|
RE 2/wk+daily AHE
|
12 weeks
|
HS, KET (Nm)
|
AMM
|
5 m walking time, one leg stand, CS, GS
|
Improved –Knee extension torque –
ex+nutr=+ 17.5%
|
Improved –(sarcopenic subgroup)
|
Improved – Max walking time in sarcopenic group
|
|
4 arms: Ex+nutr, Ex alone,
|
Ex=+1.8%
|
Ex+nutr=+10.5%
|
Ex+nutr=–15.2%
|
|
Nutr alone, Control
|
Nutr=+7.3%
|
Ex=–5.3%
|
Ex=–10.4%
|
|
Control=–13.6%
|
Nutr=+1.8%
|
Nutr=–0.9%
|
|
Control=–12.7%
|
Control=+10.5%
|
|
Zhu et al., 2019 [72]
|
Elderly adults
|
74.8±6.9 (ex+nutr)
|
113
|
130 IU vit D+8.61 g protein, 1.21 g
B-methylbtyrate, 0.21 g omega-3 fatty acid
|
90 min group training 2/wk+1 AHE
|
12 weeks
|
HD, LE kg
|
Upper and lower limb muscle mass kg, ASM/height2
(kg/m2)
|
GS, CS
|
Improved
|
Improved – ExS LLMM:+2.5%
|
Improved –ExS CS: –26.6%
|
|
74.5±7.1
|
3 arms
|
LE ExS:+28.5%
|
ExS ULMM:+2.0%
|
Ex CS=–22.8%
|
|
(ex alone)
|
LE Ex:+24.2%
|
|
5 chair stand: ExS –26.6%
|
Abbreviations: AC – arm circumference; AHE – at
home exercise; AMM – appendicular muscle mass; ASM –
appendicular skeletal mass; CC – calf circumference; CS
– chair stand test; DMS – dynamic muscle strength; Ex
– exercise therapy; GS – gait speed; HBRE – home
based resistance exercise; HS – handgrip strength; IKE –
isometric knee extension; KET – knee extension torque; LE
– leg extension strength; LP – leg press; LBM –
lean body mass; MS – muscle strength; Nutr – nutrition
supplement; RE – resistance exercise; RSMM – relative
skeletal muscle mass; SMMI – skeletal muscle mass index; SPPB
– short physical performance battery test; STS – sit to
stand; TLM – total lean mass; TUG – timed up and go
test.
Effect of vitamin D supplementation alone on non-sarcopenic
participants
Muscle strength: From the literature research, three trials [54]
[56]
[57] were identified for vitamin D supplementation
alone on non-sarcopenic individuals, of which one had additional exercise
therapy [56] (see [Table
1]). The participants were considered to be at risk of developing
sarcopenia, namely post-menopausal women [56]
[57]; and pre-sarcopenic participants [54]. No improvements were found in handgrip
strength in any of the trials [54]
[56]
[57], but
researchers noted increases in lower limb strength in two of the trials [56]
[57]. Cangussu et
al. [57], who supplemented vitamin D at a dose of
1,000 IU/day for 9 months, reported no significant alteration of grip
strength compared to the baseline measurement or the placebo group, yet noted a
25.3% increase from baseline of the chair rising test compared to the
baseline measurement, which was indicative of improved strength and physical
function. Hajj et al. [54] found an increase in
handgrip strength of 3.2% from baseline by supplementing vitamin D at a
dose of 10,000 IU three times per week for 6 months, but this finding was not
significant relative to the placebo group, while Verschueren et al. [56] (who supplemented vitamin D at a dose of 880
IU/day and 1600 IU/day for 6 months) reported a significant
increase in dynamic knee extension strength of 6.4% from baseline, for
dynamic muscle strength only. An increase of 7.9% from baseline was
found overall in dynamic muscle strength in the study arm supplemented with 1600
IU/day vitamin D, while this increased by 6.3% in the study arm
with 880 IU/day. However, the evidence on the effect of vitamin D on
knee extension strength in pre-sarcopenic individuals is limited tο a
single study [56]. The improvement in this
measurement could perhaps be explained by the additional exercise therapy that
participants in this study received (whole-body vibration training three times
per week). Therefore, there is no robust clinical evidence to allow us to
conclude that vitamin D alone improves leg strength in those at highest risk of
developing sarcopenia, and there is also no conclusive evidence to suggest that
vitamin supplementation significantly improves grip strength. Supplementation of
vitamin D for 9 months [57] did not result in
improved outcomes in grip strength compared to a 6-month supplementation period
[54]
[56].
Overall, these findings suggest that vitamin D supplementation alone
(i. e. without additional protein) does not improve handgrip strength in
non-sarcopenic participants [54]
[56]
[57]. However,
vitamin D alone may have a small beneficial effect on leg extension strength at
a dose between 880–1600 IU/day [56]. In line with this, it has been suggested that a dosage
of≥800 IU/day is adequate to achieve beneficial effects on
muscle strength and balance [47].
Muscle mass: In terms of muscle mass, Hajj et al. [54] showed an improvement of 3.0% from baseline in
appendicular skeletal muscle mass, while the other two trials showed no
significant improvements [56]
[57]. The improvements seen by Hajj et al. [54] could perhaps be explained by that fact that
participants included in the study were vitamin D deficient, and vitamin D
supplementation has been shown to be beneficial in these individuals [48]
[49]
[50]
[51]
[52]. Secondly, the study by Hajj et al. [54] administered vitamin D doses of 10,000 IU of
vitamin D three times per week, which is a several-fold higher dose of
supplement and could perhaps explain the improvement compared to the other
trials by Verschueren et al. [56] and Cangussu et
al. [57]. However, Cangussu et al. [57] reported that there was a 6.8% loss of
muscle mass in the placebo group, concluding that the vitamin D supplementation
helped to prevent further loss of muscle mass. Therefore, although there were no
significant improvements in muscle mass, it cannot be ruled out whether vitamin
D is beneficial against muscle mass loss in those at the highest risk of
sarcopenia, especially when given at a higher dose.
Physical function: Physical function was not determined at all in any of
the trials except Cangussu et al. [57]. Although
this trial found a significant increase in the chair-rising test, the lack of
robust evidence does not allow us to determine whether vitamin D supplementation
is effective in improving other measures of physical function.
Effect of combined vitamin D supplementation on non-sarcopenic
participants
Muscle strength: Three studies were identified for vitamin D plus other
nutritional supplements on non-sarcopenic older adults [59]
[60]
[61], none of which included additional exercise therapy. Vitamin D in
combination with other supplements (i. e. 21 g leucine-enriched
whey protein, 9 g carbohydrates, 3 g fat [59]; and 10 g casein, 8 g whey,
2 g soy protein [60] in non-sarcopenic
participants showed no significant differences in grip strength in any of the
trials, aside from the trial by Negro et al. [61],
who co-supplemented 1,000 IU vitamin D twice daily with Essential Amino Acids
(EAA)-based multi-ingredient nutritional supplement (5,000 mg EAA,
1,500 mg creatinine, and muscle restore complex). Maximal voluntary
contraction was measured in place of grip or knee extensor strength and showed a
5.7% improvement from baseline. However, it is important to consider
that even in studies on non-sarcopenic people, where vitamin was supplemented
alone, higher doses did not consistently produce greater improvements in
strength, mass, or function. Therefore, there are no conclusive data that
vitamin D causes a significant improvement in grip strength when in combination
with other supplements, given that: no other trials in this category showed
improvement; the measure of handgrip strength was not used (making it more
difficult to compare); and the co-supplemented ingredients may have had a
significant impact on the findings. Additionally, the 1,000 IU vitamin D
supplemented twice per day is a several fold-higher dose of vitamin D than the
other trials analyzed and may have also contributed to the significant increase
in muscle strength.
Muscle mass: Meanwhile, muscle mass improved in all vitamin D
co-supplemented groups [59]
[60]
[61]. Chanet et
al. [59], who co-supplemented vitamin D 800 IU
vitamin D once per day with 21 g leucine-enriched whey protein, found a
significant improvement in skeletal muscle mass index of 2.4% from
baseline. Kang et al. [60] supplemented 800 IU
vitamin D plus 20 g protein (50% casein, 40% whey,
10% soy, and 3000 mg leucine) found a 1.2% improvement
from baseline in lean body mass, while Negro et al. [61] reported a significant improvement of 1.7% from baseline
in appendicular lean mass. Interestingly, none of these groups which showed
improvements in muscle mass included exercise as an interventional therapy.
Taken together, it can be concluded that doses of 800 IU/day of vitamin
D supplementation together with protein may have a beneficial effect in
improving muscle mass between 1.2–2.4% [59]
[60]
[61] independently of exercise. However, one needs to bear in mind
that from these studies, the mixed effects of vitamin D and protein supplements
have been obtained. Additional studies are needed to differentiate the effects
between the two strategies, as it has been indicated that protein
supplementation has a beneficial effect on improving [73] and preserving [74] muscle mass in
older adults, while the evidence around the effect of vitamin D on muscle mass
is rather inconclusive [75]
[76].
Physical function: Data on the effect of combined vitamin D
supplementation on physical function of non-sarcopenic individuals are sparse.
However, Chanet et al. [59] and Kang et al. [60] measured physical function through the SPPB,
but neither study saw any significant improvements from baseline compared to
placebo. Additional research is needed to shed further light on this aspect.
Overall, the findings from the trials analyzed suggest that vitamin D alone may
not be effective for the improvement of grip strength, muscle mass, or physical
function in those non-sarcopenic individuals but at higher risk of developing
the disease. Yet, when vitamin D is co-supplemented with protein, mixed effects
appear to prevent or improve the decline of muscle mass. This may thereby
potentially delay the onset of sarcopenia, at doses of 800–1,000
IU/day of vitamin D over 6–12 weeks [59]
[60]
[61]. However, there is still limited evidence available, and more
research is required on the effect of vitamin D both alone and combined on
sarcopenia measures in those at risk of developing sarcopenia.
Effect of combined vitamin D supplementation on sarcopenic
participants
Muscle strength: Twelve trials [55]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72] were identified for vitamin D combined
supplementation therapy on sarcopenic persons, and six of these studies [67]
[68]
[69]
[71]
[72] investigated exercise therapy as an additional
treatment ([Table 2]). Vitamin D in combination
with other nutritional supplements in sarcopenic individuals showed improvements
in handgrip strength in seven out of twelve studies [55]
[62]
[64]
[65]
[66]
[68]
[69] ([Table 2]). Abe et al. [62] co-supplemented vitamin D at 800 IU/day
with L-leucine and 6 g of either medium-chain triglycerides (MCTs) or
long-chain triglycerides (LCTs). They found that right-hand grip strength
improved by 13.1% from baseline, but only in those participants who
received vitamin D combined with MCTs. Although the net effect of vitamin D
supplementation cannot be determined in this study, MCTs are believed to improve
muscle function through the ghrelin/growth hormone axis and
mitochondrial metabolism [77]. Meanwhile, Bo et
al. [64] supplemented vitamin D at a dose of 702
IU/day, along with 22 g whey protein and vitamin E and reported
a 9.8% increase in handgrip strength from baseline (and a 13.7%
increase compared to the control group). Li et al. [65] studied the effect of nutritional supplementation composed of 250
IU vitamin D, 10 g whey protein, 300 mg EPA (Eicosapentaenoic
Acid) and 200 mg DHA (Docosahexaenoic Acid, or rhodopsin) with or
without exercise on muscle strength of sarcopenic patients. The study reported a
19.9% increase in handgrip strength in response to the nutritional
supplementation and a 14.3% increase in response to exercise alone.
Curiously, there was a 15% increase in handgrip strength when
supplementation was combined with exercise, ruling out any synergistic effects
between supplementation and exercise. Since the study published by Gkekas et al.
[47], three additional trials were published
[66]
[67]
[68], which allowed further analysis of the effect
of vitamin D supplementation on sarcopenic patients. Meanwhile, Nasimi et al.
[66] administered participants a fortified
yoghurt product with 1,000 IU/day vitamin D, 3 g beta-hydroxy
beta-methyl butyrate (a leucine protein metabolite), and 500 mg vitamin
C, and found a 30.5% improvement in handgrip strength from baseline.
Nilsson et al. [67] administered 1,000
IU/day vitamin D with 24 g whey protein, 16 g casein,
3 g creatine, and omega-3 containing fish oil to the intervention group
(which contained sarcopenic and non-sarcopenic participants) and found
significant improvements from baseline in handgrip strength by 7.8%.
When examining the effect on sarcopenic patients alone who received the
intervention in the sarcopenia subgroup analysis, muscle strength was not found
to be significantly altered compared to the baseline, so it is likely that any
significant change found in the normal analysis is due to improvements in
non-sarcopenic participants. Rondanelli et al. [69] administered participants a combined supplement of 100 IU vitamin
D, 22 g whey protein, and 10.9 g essential amino acids
(including 4 g leucine) and found a 19.2% increase in handgrip
strength from baseline over 12 weeks. In a follow-up study, the same group of
authors [68] found an improvement of 21.9%
in handgrip strength compared to baseline following a supplementation with 800
IU vitamin D twice daily, along with 20 g whey protein enriched with
leucine. Takeuchi et al. [55] co-supplemented
vitamin D at 500 IU/day with 10 g BCAA, and found an improvement
in handgrip strength, namely an increase of 40.5% from baseline. The
study by Verlaan et al. [70] supplemented vitamin
D at a dose of 800 IU/day, with 20 g whey protein and
3 g leucine, and indicated that handgrip strength was measured. However,
they did not present the change from baseline in their results. So we were
unable to include this in our analysis.
Taken together, these results indicate that when vitamin D is co-supplemented
with protein (mainly whey, casein, BCAA, or leucine), a beneficial effect is
evident for handgrip strength. In these studies, handgrip strength increased
between 9.8–40.5% when vitamin D was dosed between
100–1,000 IU/day. However, the large range of vitamin D dosage
does not allow to determine accuracy of treatments. We have not been able to
identify any correlation between vitamin D dosage and muscle strength on the
above studies (see [Fig. 3]). This indicates that
other parameters are possibly acting as interfering variables or that the
handgrip strength test was not standardized among different research
environments. Dosage recommendations for handgrip strength improvements are
difficult to determine based on these studies due to the large data variability.
The supplement with the smallest dose of vitamin D at 100 IU/day [69] showed a greater improvement in handgrip
strength than other studies that used higher doses of vitamin D [62]
[67], indicating
that co-supplemented nutrients had a more significant impact in improving
strength than vitamin D. The smaller dose of 500 IU/day [55] appeared to exert the greatest impact on
handgrip strength, but this combined effect may be attributed to the
co-supplementation with 10 g BCAA, as it has been shown that protein
supplementation alone improves muscle strength in older adults [22].
Fig. 3 Relative changes of muscle mass and strength. (A-B) Percent
changes in muscle strength and mass respectively among trials from
non-vitamin D deficient patients respectively. Percent changes were
calculated by the authors to the best of our ability based on the
original data published in individual trials. (C-D) Vitamin D dosage
does not correlate with observed changes in muscle strength and mass
(Pearson correlation coefficients).
Three studies showed no significant improvements in handgrip strength [63]
[71]
[72]. Nilsson et al. [67], Yamada et al. [71] and Zhu et al.
[72] instead reported significant improvements
in lower limb muscle or knee extension strength. However, only three trials
measured lower limb or knee extension strength; therefore, the evidence is
rather sparse limiting the interpretation of these data. Yamada et al. [71] found a 7.3% increase from baseline in
knee extension strength with 800 IU/day of vitamin D plus 10 g
whey protein. When supplementation was combined with exercise knee extension
strength increased by 17.5% from baseline, while the knee extension
strength of the control group decreased by 13.6%. Zhu et al. [72] studied the effect of supplementation with 130
IU/day of vitamin plus: 8.61 g protein, 1.21 g
B-methylbutyrate, 0.21 g omega-3 fatty acid, with or without exercise on
leg extension strength. They reported a 28.5% increase (from baseline)
in strength in response to supplementation plus exercise training for 12 weeks,
and an increase of 24.2% in response to exercise training alone.
Finally, in the trial by Nilsson et al. [67]
(where participants were supplemented with 1,000 IU/day vitamin D)
muscle strength on the leg press improved by 14.8%, while knee extension
strength did not change significantly. Taken together, these trials indicate
that vitamin D plus protein supplementation may increase limb strength even when
handgrip strength tests did not show improvement. However, there appears to be a
discrepancy in the results as there was a greater increase with 130
IU/day of vitamin D [72] than 800
IU/day vitamin D [71] and 1,000
IU/day vitamin D [67], indicating that the
effect may be due to the co-supplemented protein. Another contributing factor
may have been the age of the participants, as in the trial by Zhu et al. [72] the participants were 10 years younger than in
the trial by Yamada et al. [71]. There is some
evidence to suggest that younger individuals respond better to protein
supplementation, as it has been indicated that older adults have blunted
response to anabolic stimuli [78]
[79].
Muscle mass: In terms of muscle mass, ten studies showed improvement [55]
[63]
[64]
[65]
[67]
[68]
[69]
[70]
[72]. Measurements of muscle mass varied between
studies and were measured by either appendicular muscle mass (AMM) or
appendicular skeletal muscle mass (ASMM) [63]
[64]
[65]
[67]
[68]
[70]
[71], relative
skeletal muscle mass index (SMMI) or relative skeletal muscle mass (RSMM) [64]
[66]
[68]
[69], total lean
mass (TLM) [67], or calf circumference [55]. Bauer et al. [63], in the PROVIDE study, co-supplemented 800 IU/day vitamin
D with 20 g whey protein enriched with 3 g leucine, 9 g
carbohydrates, and 3 g fat, and found an estimated 1.3% increase
in AMM from baseline (as calculated by us from a results bar graph), and a
1.0% gain compared to the control group. Rondanelli et al. [68] also reported a 6.3% improvement in AMM
from baseline and a 6.5% increase in SMMI. Verlaan et al. [70] also found improvements in AMM by 1.9%
from baseline. Yamada et al. [71] reported
significant improvements in AMM in the exercise plus nutrition group in the
sarcopenic subgroup (however, due to insufficient sample size in the sarcopenia
subgroups these findings may be subject to type 2 error), in which AMM improved
by 10.5% from baseline. Nutrition alone showed a significant improvement
of 1.8% from baseline, while, interestingly, exercise alone was not
effective in preventing the loss of muscle mass, and this group showed a
decrease of 5.3% from the baseline measurement. Zhu et al. [72] reported a significant improvement in
exercise-supplementation-group of 2.1%, which was significant when
compared to the placebo group and exercise-alone group. Li et al. [65] found improvement in AMM by 4.7% from
baseline in response to nutrition alone, by 3.5% in response nutrition
plus exercise and a 2.2% in response to exercise alone. Nilsson et al.
[67] found that muscle mass in the sarcopenic
subgroup analysis significantly improved from baseline when sarcopenic
participants received the vitamin D combined nutritional supplement. TLM
improved by 3.4% from the baseline, while ALM improved by 4.1%
from the baseline. In the study by Bo et al. [64],
RSMM increased significantly from compared to the control group by 3.1%,
yet the difference of 1.4% from baseline was not found to be a
significant increase.
Rondanelli et al. [69] found that RSMM improved by
3.2% from baseline. Takeuchi et al. [55]
reported an increase in calf circumference of 3.8%. Meanwhile, muscle
mass was unaltered in the intervention populations of three studies [62]
[64]
[66]. These results indicate that vitamin D plus
protein supplementation results in significant improvements in muscle mass. This
is supported by the conclusions of a recent meta-analysis [47] regarding the beneficial effect of vitamin D
supplementation in combination with other nutritional supplements in improving
muscle mass and strength. However, the trial by Abe et al. [62] did not find improvements. There is a large
range of muscle mass increase from 1.3–10.5% at doses of vitamin
D 100–1,000 IU/day. The largest increase in muscle mass was
found by Yamada et al. [71], when 800 IU vitamin D
was supplemented with 10 g whey protein plus exercise for 12 weeks. A
large increase also seen with Rondanelli et al. [68] who administered 800 IU vit D 20 g whey plus exercise;
the smaller effect may be due to the shorter dosage time period of 4–8
weeks. From this analysis, 800 IU/day vitamin D may be the most optimal
dose to see the greatest improvements in muscle mass (when coupled with
exercise). However, the evidence is still slightly unclear as significant
improvements were found by Rondanelli et al. [69]
despite participants receiving the smallest dose of 100 IU/day vitamin
D. Here, it is arguable that the increase in muscle mass may have been brought
about by the 22 g whey protein supplemented in the study [69].
Physical function: Muscle function has been assessed differently among
trials by various approaches including walking speed, gait speed, TUG test,
SPPB, five times sit-to-stand test, chair stand test, 5-min walking time. Six
studies reported significant improvements in physical function of sarcopenic
patients [62]
[66]
[67]
[68]
[71]
[72]. Abe et al. [62] found an increase
in walking speed of 12.5% from baseline, while Nasimi et al. [66] found a 10.7% improvement in 4-min gait
speed. Nilsson et al. [67] found improvements in
the sarcopenic subgroup analysis in the 6-metre walk test of 7.4% from
baseline, and improvements in the 4-step chair climb test of 20.3% from
the baseline measurement. Rondanelli et al. [68]
found improvements of 28.0% in the chair stand test, 12.5% in
the TUG test, and 65.0% in SPPB, without any improvements in the 4-min
gait speed test. Yamada et al. [71] found a
10.4% improvement in 5-min walking time in response to a 12-week
exercise training program from baseline, 15.2% improvement in response
to exercise training plus supplementation (i. e. 800 IU/day of
vitamin D plus 10 g whey protein), while supplementation alone resulted
in significantly higher test time by 5.6% from baseline. This study
failed to report any improvements in one leg stand and 5 chair stand tests. Of
note, in the placebo group the time worsened by 10.5% from baseline. Zhu
et al. [72] found an improvement in the five-chair
stand test by a 22.8% in response to exercise training and a
26.6% in response to exercise training plus supplementation
(i. e. 130 IU/day of vitamin plus: 8.61 g protein,
1.21 g B-methylbtyrate, 0.21 g omega-3 fatty acid) from
baseline. However, there were not any cumulative effects of exercise plus
supplementation on muscle function. Physical function was not assessed in two
trials [55]
[69].
Overall, the evidence for the effect of vitamin D on physical function is
limited. Half of the trials included in this review investigating sarcopenic
participants failed to measure physical function at all or did not report
improvements in physical function [55]
[63]
[64]
[65]
[69]
[70]. However, discrepancies in the use of measured
aspects of physical function among trials and inconsistent results on the role
of vitamin D perplex the comparison and interpretation of findings. As a result,
there is not abundant evidence that vitamin D consistently improves physical
function in sarcopenic individuals, especially as any improvements found [62]
[66]
[67]
[68]
[71]
[72] may well be
attributed to additional variables such as exercise training or co-supplemented
protein.
