Effect of Vitamin D Supplementation on Muscle Strength

CLINICAL INVESTIGATIONS

Effect of Vitamin D Supplementation on Muscle Strength, Gait and Balance in Older Adults: A Systematic Review and Meta-Analysis Susan W. Muir, PhD,* and Manuel Montero-Odasso, MD, PhD, AGSF*†‡

OBJECTIVES: To systematically review and quantitatively synthesize the effect of vitamin D supplementation on muscle strength, gait, and balance in older adults. DESIGN: Systematic review and meta-analysis. SETTING: MEDLINE, EMBASE, Cochrane Library, bibliographies of selected articles, and previous systematic reviews were searched between January 1980 and November 2010 for eligible articles. PARTICIPANTS: Older adults ( 60) participating in randomized controlled trials of the effect of supplemental vitamin D without an exercise intervention on muscle strength, gait, and balance. MEASUREMENTS: Data were independently extracted, and study quality was evaluated. Meta-analysis using a fixed-effects model was performed and the I2 statistic was used to assess heterogeneity. RESULTS: Of 714 potentially relevant articles, 13 met the inclusion criteria. In the pooled analysis, vitamin D supplementation yielded a standardized mean difference of 0.20 (95% confidence interval (CI) = 0.39 to 0.01, P = .04, I2 = 0%) for reduced postural sway, 0.19 (95% CI = 0.35 to 0.02, P = .03, I2 = 0%) for decreased time to complete the Timed Up and Go Test, and 0.05 (95% CI = 0.11 to 0.20, P = .04, I2 = 0%) for lower extremity strength gain. Regarding dosing frequency regimen, only one study demonstrated a beneficial effect on balance with a single large dose. All studies with daily doses of 800 IU or more demonstrated beneficial effects on balance and muscle strength. CONCLUSION: Supplemental vitamin D with daily doses of 800 to 1,000 IU consistently demonstrated beneficial effects on strength and balance. An effect on gait was not From the *Division of Geriatric Medicine, Department of Medicine, Parkwood Hospital, University of Western Ontario, †Gait and Brain Laboratory, Lawson Health Research Institute, and ‡Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. Address correspondence to Manuel Montero-Odasso, Parkwood Hospital, Division of Geriatrics Room A-280, 801 Commissioners Rd E., London, Ontario, Canada N6A 5A5. E-mail: [email protected]

demonstrated, although further evaluation is recommended. J Am Geriatr Soc 2011.

Key words: vitamin D; aged; systematic review; randomized controlled trials; muscle strength; balance; gait

V

itamin D deficiency has recently gained much attention because of its association with cardiovascular disease, cancer, falls, fractures, and mortality.1–3 Older adults are especially at risk of developing vitamin D deficiency because of low sunshine exposure, less skin capacity to synthesize vitamin D, poorer absorption of vitamin D with less activation in the kidneys and peripheral tissues, and fewer or lower expression of vitamin D receptors in peripheral tissues.4–7 In older adults, vitamin D deficiency has been associated with important determinants of disability, including poor physical performance, low muscular strength, cognitive impairment, falls, and fractures.8–15 Falls and fractures are also strongly associated with muscle weakness and gait and balance deficits.16 Because muscle weakness is a feature of the clinical syndrome of vitamin D deficiency, it has been postulated that vitamin D deficiency may precipitate and potentiate muscle weakness and functional decline in older people.17 During the last decade, it has been demonstrated that vitamin D supplementation reduces fall risk in older adults when doses of 700 to 1,000 IU per day are used.18,19 This beneficial effect on fall reduction in isolation from exercise prescription seems to occur through action on neuromuscular function.17,18 Vitamin D receptors (VDRs) are present in several tissues throughout the body, including bone, muscle, and brain,20,21 and their expression and activity decline with aging.20 Serum levels of vitamin D decline significantly with aging, and this has been associated with reduced VDR activation and reduced muscle cell function.21 This low expression and activity has been well

DOI: 10.1111/j.1532-5415.2011.03733.x

JAGS 2011 © 2011, Copyright the Authors Journal compilation © 2011, The American Geriatrics Society

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documented in muscle, which affects the response of myocytes to vitamin D.21 Additionally, VDRs have been located in the human cortex and hippocampus and at a cellular level are present in neurons and glial cells.20 Vitamin D deficiency in older people has been associated with impairments in the central nervous system, including cognitive decline and balance problems,22 and in the peripheral nervous system, including reduction of nerve conduction velocity.23 It has been suggested that vitamin D affects neuromuscular control and coordination24 and may act as a neurosteroid hormone.25 Based on these age-associated changes, there is a compelling rationale to believe that there is a beneficial effect of vitamin D supplementation on neuromuscular function in older adults, particularly when high doses are used.17 A recent review of vitamin D in adult health and disease supported fall risk reduction but did not comment on physical function effects.26 Previous systematic reviews on the effect of vitamin D supplementation on muscle function reported insufficient evidence to support the therapeutic use of vitamin D alone.8,27 The use of vitamin D in combination with calcium supplementation was noted to have some supporting evidence, although more-definitive work was recommended.27 A potential explanation for these inconclusive findings could be related to variation in important research elements, such as heterogeneity in study quality, and variability in assessment methods of physical performance. Most importantly, and in light of the recent meta-analysis findings on fall risk, an important factor to consider is the dose and treatment regimen of vitamin D evaluated in each study.18 As was hypothesized in a previous review in 2005,17 higher doses of vitamin D, at least 800 IU daily, may be necessary to improve muscle strength- and physical performance-related outcomes in older adults. Therefore, the objective of this systematic review was to assess the efficacy of vitamin D supplementation, including variations in dose and treatment regimen, on muscle strength, balance, and gait in older adults.

METHODS Data Sources and Search Strategy A detailed literature search, without language restriction, was conducted to identify articles published between January 1980 and November 2010. The following electronic databases were searched: MEDLINE, PubMed, EMBASE, and the Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, and Cochrane Controlled Trials Register). The following Medical Subject Headings (MeSH) and subject terms or key words were used: trials (randomized controlled trial, single blind method or procedure, double blind method or procedure, random allocation, randomization), elderly (aged; aged, 80 and over), vitamin D (cholecalciferol, ergocalciferol), accidental falls, gait, gait disorder, postural balance, balance impairment, and muscle strength. An iterative process was used in the database searches to ensure that all relevant articles had been

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obtained. A manual search of bibliographic references of extracted articles and existing reviews was also conducted.

Study Selection Abstracts were screened to identify potentially relevant articles. After retrieving the full text, an article was considered relevant if it met the following criteria: randomized controlled trial of supplemental vitamin D or associated metabolite, with or without calcium, with a placebo or standard treatment arm; study did not include an exercise intervention; study population consisted of older adults, age 60 and older; and physical performance measures of muscle strength, gait, or balance were measured at baseline and study termination. The two authors independently evaluated each article to determine whether it met the inclusion criteria for full review.

Methodological Quality Assessment The two authors independently assessed the methodological quality of included articles using the Downs and Black scale,28 a validated, reliable instrument for evaluating clinical trials. The scale has 27 questions grouped into five sections: reporting; external validity; internal validity, bias; internal validity, confounding; and power. The aggregated maximum possible score is 32, with a higher score indicating greater methodological quality. When rating discrepancies occurred, the two reviewers resolved differences by consensus to achieve a single score. The quality of reporting was evaluated using the CONSORT guidelines.29 Interrater reliability of the methodological assessment of the ratings in this study, using the intraclass correlation coefficient (ICC), were 0.87 for the Downs and Black score and 0.85 for the CONSORT score.

Data Extraction Articles selected for full review had the following information extracted: authors, country, date of publication, sample size, percentage of total sample that was female, percentage that completed the study, mean age, sample population, vitamin D dose regimen, treatment adherence, study duration, and name of the physical performance measures (Table 1). The inclusion and exclusion criteria of study participants within the selected articles were also extracted (data not presented). Serum levels of 25-hydroxyvitamin D (25(OH)D) were also extracted (before and after treatment) and qualitatively categorized2 as deficiency (D) at less than 20 ng/L or less than 50 nmol/L, insufficiency (I) at 21 to 29 ng/L or 50 to 75 nmol/L, and normal (N) at 30 ng/L or more or 75 nmol/L or more (Table 2).

Data Synthesis and Analysis A fixed-effects model (inverse variance method) was used for the meta-analysis. A summary measure of the mean difference or the standardized mean difference with a 95% confidence interval (CI) was calculated for balance, gait, and muscle strength. Statistical analysis for heterogeneity

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EFFECTS OF VITAMIN D ON BALANCE AND STRENGTH

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Table 1. Summary of Studies Meeting the Selection Criteria for Inclusion in the Systematic Review

Study

Zhu43

Sample Size, n (Female, %)

Study Population

302 (100)

CD

Age Mean ± Standard Deviation

Study Duration (Months)

Adherence, %

76.9

12

86.8

MoreiraPfrimer39 Pfeifer41

56 (79)

ID

78.3

6

NR

242 (75)

CD

76.5

20

93

Grieger37

115 (65)

ID

NR

6

BischoffFerrari31 Bunout35

122 (100)

ID

85.7

3

Placebo: 82 Multivitamin: 91 NR

96 (90)

CD

77.0

9

92

Sato42 Dhesi24

96 (100) 139 (78)

ID CD

74.2 76.8

24 6

NR NR

Gallagher11

489 (100)

CD

72

36

NR

Bischoff34 Latham38

122 (100) 243 (53)

ID ID

85.7 79.1 ± 6.9

3 6

NR 100

Pfeifer40

148 (100)

CD

74.0 ± 1.0

2

95

Grady36

98 (50)

CD

79.2

6

>95

Physical Performance Measure*

Methodological Quality Rating (CONSORT Guidelines29/ Downs and Black Scale28)

Strength: a, b, c, d, e, f, g Balance: TUG Strength: c, e

20/26

Strength: c Balance: body sway, TUG Strength: h Balance: TUG

22/17

Balance: static, dynamic Strength: c, h Balance: body sway, TUG Gait: 12 minute walk Strength: e, f Strength: c Balance: body sway Strength: h, i Gait: 5-m timed walk Composite score† Strength: c Balance: BBS, TUG Gait: 4 m timed walk Balance: body sway Strength: h, j

30/18

13/8

20/11

11/6

23/14 22/15

10/7

30/17 29/22

25/15 14/9

* (a) maximal isometric ankle dorsiflexion, (b) maximal isometric knee flexion, (c) maximal isometric knee extension, (d) maximal isometric hip abduction, (e) maximal isometric hip flexion, (f) maximal isometric hip extension, (g) maximal isometric hip adduction, (h) grip strength, (i) timed chair stands, (j) isokinetic knee flexion and knee extension. † Composite score from Timed Up and Go Test (TUG), knee flexor strength, knee extensor strength, and grip strength. CD = community dwelling; ID = institutional dwelling; NR = not reported; BBS = Berg Balance Scale.

used the chi-square test for heterogeneity and the I2 statistic to quantify total variation across studies attributable to heterogeneity.30 Meta-analysis results are presented as forest plots. Qualitative descriptors of the effect sizes obtained were less than 0.3, small; 0.4 to 0.8, moderate; and greater than 0.8, large.31 Statistical analyses were performed using the software program Review Manager (RevMan) 5.0 (The Nordic Cochrane Centre, Copenhagen, Denmark).

RESULTS Study Characteristics Seven hundred fourteen abstracts, including studies with duplicate entries in the multiple databases, were identified as potentially relevant based on the important search terms

and the hand search of bibliographic references. After the initial screening of abstracts, 39 full text articles were retrieved for detailed analysis (Figure 1; Appendix 1, the list of retrieved articles excluded from the detailed analysis, is available on-line). Thirteen articles met the inclusion criteria (Table 1), of which two were derived from the same data source, but each presented different measures of physical performance, yielding 12 independent data samples.11,24,32–42 The average age of participants was 78 ± 4.1, with an age range, where reported, of 63 to 99 across all studies (Table 1). Sample size ranged from 56 to 302, and only three studies24,38,42 reported information on ethnic or racial composition of the samples, Caucasian being the most common at 64% to 100% of the samples. Seven studies evaluated community-dwelling older adults, and six evaluated institution-dwelling older adults. Three stud-

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Table 2. Included Studies Stratified According to Vitamin D Dose and Treatment Regimen for the Outcomes of Muscle Strength, Balance, and Gait Serum Vitamin D levels* (nmol/L)

Study

Single dose Dhesi24 Latham38

Vitamin D Regimen

C) Placebo T) Ergocalciferol 600,000 IU C) Placebo T) Calciferol 300,000 IU

Monthly dose C) 1,000 mg calcium MoreiraT) 1,000 mg calcium + cholecalciferol Pfrimer39 (150,000 IU for 2 months then 90,000 IU for 4 months) <800 IU per day Grieger37 C) Placebo T) Multivitamin—360 mg calcium, cholecalciferol 400 IU C) 800 mg calcium Bunout35 T) 800 mg calcium + cholecalciferol 400 IU Gallagher11 C) Placebo T) Calcitriol 20 IU C) Placebo Grady36 T) Calciferol 20 IU 800 IU per day C) 1,000 mg calcium + placebo Zhu43 T) 1,000 mg calcium + ergocalciferol 1000 IU C) 1,000 mg calcium Pfeifer41 T) 1,000 mg calcium + cholecalciferol 800 IU C) 1,200 mg calcium BischoffT) 1,200 mg calcium + cholecalciferol 800 IU Ferrari33‡ C) Placebo Sato42 T) Ergocalciferol 1,000 IU C) 1,200 mg calcium Bischoff34 T) 1,200 mg calcium + cholecalciferol 800 IU C) 1,200 mg calcium Pfeifer40 T) 1,200 mg calcium + cholecalciferol 800 IU

Prestudy

Poststudy

47.42 37.44 24.96 26.71

NR NR 31.45 (D) 43.68 (D)

(D) (D) (D) (D)

Measure of Physical Performance (BetweenGroup Postintervention Differences) P-Value

Balance

Gait

Muscle Strength

Summary Score†

<.02

–

>.05§

–

>.05§

>.05§

>.05§

–

39.5 (D) 45.9 (D)

51.8 (I) 86.6 (N)

–

–

<.001

–

35.5 (D) 35.7 (D)

29.5 (D) 63.13 (I)

>.05§

–

>.05§

–

32.70 (D) 30.95 (D) NR NR 65.7 (I) 60.4 (I)

36.19 (D) 64.40 (I) NR NR NR NR

>.05§

.045

>.05§

–

–

>.05§

>.05§

–

–

–

>.05

–

44.2 (D) 44.9 (D) 54.00/ (I) 55.00 (I) 36.44 (D) 41.68 (D) 24.46 (D) 24.46 (D) 28.95 (D) 30.70 (D) 24.63 (D) 25.65 (D)

44.9 (D) 59.9 (I) 57.00 (I) 84.00 (N) 32.95 (D) 61.90 (I) 13.23 (D) 83.37 (N) 28.45 (D) 65.40 (I) 18.30 (D) 40.46 (I)

<.05

–

<.05

–

<.05

–

<.05

–

>.05

–

–

–

–

–

<.01

–

–

–

–

.009

<.04

–

–

–

*

Serum vitamin D levels identified as deficiency (D) (<20 ng/L or <50 nmol/L), insufficiency (I) (21–29 ng/L or 50–75 nmol/L), and normal (N) ( 30 ng/ L or >75 nmol/L).2 † Summary score based on Timed Up and Go Test, knee flexor strength, knee extensor strength, and grip strength in previous study.34 ‡ Same data used as34, but different measure of physical performance analyzed and reported. § Results not statistically significant but level of significance not reported. NR = not reported; C = control group; T = treatment group; LE = lower extremity.

ies24,38,42 excluded participants with medical conditions that would impair postural stability or the physical performance tests. To evaluate the isolated effects of vitamin D supplementation on balance, gait, and muscle strength, studies with an investigational exercise routine with vitamin D were excluded from this review. Two studies included analyses of the effects of vitamin D supplementation alone and in combination with an interventional exercise program;33,37 only the results from the study arms of the vitamin D supplementation alone and the placebo group were extracted for analysis. There were multiple sources of heterogeneity of study design identified a priori that could potentially produce clinically relevant variation in the results across studies: study quality (Downs and Black scores), vitamin D dosing regimen (size of dose, frequency of administration,

combination with calcium supplementation and duration of treatment), and 25(OH)D levels.

Study Quality Assessment Downs and Black scores ranged from 10 to 30 (Table 1). Methodological limitations were present primarily in the areas of lack of detail on the randomization process, lack of sample size calculations, and failure to provide sufficient detail on study participants, in particular, participants who were lost to follow-up. All studies used outcome measures with references for reliability and validity in measuring balance, gait, or muscle strength. There was a wide variation in the quality of information reporting, evaluated using the CONSORT guidelines. The most common deficiencies were related to the randomization mechanisms, flow of participants through

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supplementation and achieved improvements in physical outcomes of interest after treatment: muscle strength, gait, or balance function.38,40,41 Six studies showed an increase from the deficiency to insufficiency level after intervention,32–34,36,39,42 and four demonstrated a significant positive effect on physical function.33,34,39,42 One study was not able to improve the deficient serum levels with treatment and did not demonstrate a positive effect on physical function outcomes.37

Meta-analysis

Figure 1. Flowchart of literature search.

the study, and lack of a clear statement of the blinding of participants and those assessing the outcomes. Because the earliest study,35 published before 2001, did not receive the lowest score, there does not appear to be a bias in evaluating earlier studies more severely using the CONSORT guidelines.

Vitamin D Dosing Regimens The results of the studies are presented in Table 2, stratified according vitamin D dose and regimen. Statistically significant improvements in physical performance were noted in nine studies.24,33,34,38–42 Only one study demonstrated a beneficial effect on balance of a single large dose of vitamin D.24 All studies with doses of 800 to 1000 IU per day demonstrated beneficial effects on balance39,40,42 and lower extremity muscle strength.33,40,41 Vitamin D doses of 800 to 1,000 IU had beneficial effects in the two general populations of community-dwelling and institutional-dwelling older adults. Six of the eight studies that showed a beneficial neuromuscular effect included calcium supplementation in the regimens.34,35,39–41,43

Serum 25(OH)D levels Twelve of the 13 studies included in this systematic review reported mean serum levels of 25(OH)D at baseline (Table 2). Serum levels were in the deficiency range (<50 nmol/L) for 10 of these 12 studies24,33–35,37–40,42,43 and the insufficiency range (50–75 nmol/L) for two studies.36,41 Of the 12 studies with serum levels at baseline, only 10 reported mean serum levels at the end of the intervention period.32–34,36–42 In the intervention groups, three studies reached normal serum levels with vitamin D

Meta-analysis was performed for the outcomes of balance (body sway, Timed Up and Go (TUG) Test), lower extremity muscle strength (knee extension), and grip strength without stratification according to dose or treatment regimen (Figure 2). The summary standardized mean difference, derived from studies with a total of 207 participants, on postural sway yielded a value of 0.20 (95% CI = 0.39 to 0.01, P = .04), indicating a reduction in sway.24,34,40 Three studies,34,40,42 with a total of 274 participants, showed a decrease in time to complete the TUG Test of 0.19 (95% CI = 0.35 to 0.02, P = .03). A positive gain in knee extension strength was found (mean difference for knee extension strength = 0.05, 95% CI = 0.11 to 0.20, P = .04).34,40 A sensitivity analysis was performed for balance sway, which removed one study34 because of its low quality of reporting score. The revised summary standardized mean difference was not statistically significant ( 0.17, 95% CI = 0.38 to 0.03), indicating that results were not robust to the removal of a study with a small sample size. Nine studies could not contribute data to the metaanalysis because of the specific limitations in the published data: mean values by treatment groups at follow-up not reported in text but given in graphical format11,32,33,35,37 and median values of treatment groups provided.37

DISCUSSION This systematic review has demonstrated that balance and muscle strength are improved with daily supplemental vitamin D doses of 800 to 1,000 IU. The magnitude of the treatment effect was small for balance, as measured according to body sway and the TUG Test, and lower extremity muscle strength in the meta-analysis. An effect on gait, measured as improvement in distance walked, was not supported. The improvement in the TUG Test can be seen as a marker of improved gait performance, although studies that explicitly evaluated gait were of lower methodological quality and used low doses of vitamin D, so further evaluation of gait effects in high-quality randomized controlled trials are recommended. The beneficial effects on balance and strength found in the present review provide a mechanism to explain the results from the recent meta-analysis that established vitamin D alone in doses of 700 to 1,000 IU a day in older adults reduced fall risk and rate of falls.18 In addition, three studies24,38,42 specifically excluded participants with medical conditions that impair postural stability or would affect physical performance tests. The exclusion of these individuals would attenuate the potential of finding a

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Figure 2. Forest plots for summary standardized mean difference for (A) balance sway, (B) Timed Up and Go Test, and (C) lower extremity muscle strength.

treatment effect; the individual studies found statistically significant effects on balance and strength, which probably represent conservative estimates of effect. Only five studies reported information on disease burden of individuals, which may have an important relationship with an effect on the physical performance outcomes and limits comparison of effects between studies of comparable treatment regimens or study populations. Evidence has also found vitamin D supplementation that increased serum concentrations of 25(OH)D to normal levels, in excess of 30 ng/mL or 75 nmol/L2, was consistently associated with improvement in muscle strength and balance. This may explain the mechanistic basis of fall prevention with higher doses of vitamin D. Optimal fall prevention has been found to occur in trials that achieved mean serum concentrations at 75 to 100 nmol/L, whereas low doses of vitamin D (<800 IU) or achieved serum 25 (OH)D concentrations less than 60 nmol/L did not reduce falls.18 One interesting and possible explanation for this finding could be related to the hypothesis that serum concentration levels of 80 to 100 nmol/L enhance autocrine and paracrine release of vitamin D by muscle tissue and that this counteracts the negative effect of parathyroid hormone on muscle.43–46 The associations between vitamin D supplementation and improvement in muscle strength and balance are poorly understood. It has been suggested that not only muscle strength, but also improvement in other dimensions

of the muscle, such as muscle power or muscle contraction speed may mediate the effect of vitamin D on physical performance measures. In addition to the effect on muscle function, vitamin D also affects neuromuscular control and neural coordination, and there is growing evidence supporting a neurotrophic effect of vitamin D.23 For instance, vitamin D deficiency has been associated with a reduction of nerve conduction, and there are reports that vitamin D appears to regulate neurotransmission by acting like a neurosteroid hormone.25 Therefore, improvements in balance performance could be mediated through a neural effect. The results of the current study also suggest that a high single dose of vitamin D or high weekly or monthly doses were not as consistent in demonstrating improvements in physical performance measurements as daily high doses. This finding is consistent with a recent clinical trial that failed to show an effect of a very high single dose of vitamin D (500,000 IU) on falls prevention.47 This emphasizes the importance of considering not only the effect of dose size, but also the dosing interval on the effect of vitamin D on neuromuscular function. It was not possible to determine whether calcium in combination with vitamin D provided greater benefits to physical performance than vitamin D supplementation alone; further research is necessary to address this question. Since the first systematic review on the effect of vitamin D supplementation on physical performance measures,27 the pool of studies found eligible for evaluating

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this association has increased from seven to 13. The number of studies included in this review is consistent with recent systematic reviews of vitamin D supplementation to prevent falls and fractures in older adults.4,18,19,48 The larger number of studies available for this systematic review may have finally allowed the ability to see a pattern according to dose and treatment regimen. Unfortunately, the meta-analysis of treatment effects of individual physical performance levels was not able to use data from all studies and could not be stratified according to vitamin D dose and treatment regimen. Considering this limitation, summary values of positive effects were found for improving performance on balance sway testing and the TUG Test. Unlike the current study, previous systematic reviews evaluating the effects of supplemental vitamin D on measures of physical performance found limited evidence to support a treatment effect.8,27 The inclusion of observational studies and cross-sectional studies in the earlier reviews, which precludes establishing a temporal order between the exposure and outcome, may also partially explain this discrepancy.8 Another limitation of the previous reviews was the absence of an evaluation of potential sources of heterogeneity in study design that could influence and produce clinically relevant differences. The largest study of the effect of vitamin D supplementation on physical performance measures did not find an association for improved strength.49 That study was not included in this systematic review because the sample consisted of women aged 50 to 79, an age range outside that typically defined as elderly. In addition, that study did not report pre- or postintervention serum 25(OH)D levels, and the dose regimen was 400 IU daily. Reflecting on the results of the current meta-analysis, there are several possible explanations for the lack of an observed effect, the most prominent being the dose of supplemental vitamin D used in the study. The present systematic review has several strengths. A detailed research protocol was included, with no language exclusion, and an a priori specification and evaluation of potential study design considerations. Sensitivity analyses were performed in the meta-analysis to evaluate the robustness of the results for the influence of individual studies on the pooled estimates. This is the first systematic review on this topic that has performed a meta-analysis to provide a quantitative summary of the effect of vitamin D supplementation on measures of physical performance. There are some limitations to this systematic review that should be noted. One person screened abstracts for full evaluation, and this process could have introduced bias, although all references from previous systematic reviews were screened for a full evaluation performed independently by the two evaluators. In conclusion, it was found that vitamin D supplementation in doses of 800 to 1,000 IU/d have a beneficial effect on balance and muscle strength. An effect on gait was not found, although the studies that evaluated gait were of lower methodological quality and used low doses of vitamin D. Dose regimen may play an important role in the neuromuscular effect of vitamin D because daily regimens showed a consistent beneficial effect, emphasizing the importance of the dosing interval on the effect of vitamin D on neuromuscular function. Because of variations within the research, further well-designed randomized con-


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trolled trials are needed to establish clearly the presence and magnitude of the effect of supplemental vitamin D on muscle strength, gait, and balance.

ACKNOWLEDGMENTS We are grateful for the review of the manuscript by Judy McCallum, Department of Geriatric Medicine, University of Western Ontario, London, Ontario, Canada. Conflict of Interest: This study was funded by a peerreviewed grant from the Canadian Institutes of Health and Research (CIHR) and the Institute of Aging, Canada, and by a research grant from the Program of Experimental Medicine at the Department of Medicine, University of Western Ontario, London, Ontario, Canada. Dr. Muir is recipient of the Post-doctoral Award from the Alzheimer Society of Canada Research Program. Dr. Montero-Odasso’s research Program on Gait and Cognition is supported by operating grants from the Drummond Foundation, Montreal; the Physician Services Incorporated Foundation (PSI), Toronto; and from the CIHR. Dr. Manuel Montero-Odasso is the first recipient of the Schulich Clinician Scientist Award (2008–2011) and recipient of the CIHR New Investigator Award (2011–2016). Author Contributions: SWM: Study design, data collection, statistical analysis, interpretation of data, drafting of the manuscript, and revising it for important intellectual content. MMO: Study conception, interpretation of data, obtaining grant support, drafting of manuscript and revising it for important intellectual content. Sponsor’s Role: The sponsor did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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14. Wicherts IS, van Schoor NM, Boeke AJ et al. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab 2007;92:2058–2065. 15. Zamboni M, Zoico E, Tosoni P et al. Relation between vitamin D, physical performance, and disability in elderly persons. J Gerontol A Biol Sci Med Sci 2002;57A:M7–M11. 16. Panel on Prevention of Falls in Older Persons, American Geriatrics Society and British Geriatrics Society. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons. J Am Geriatr Soc 2011;59:148–157. 17. Montero-Odasso M, Duque G. Vitamin D in the aging musculoskeletal system: An authentic strength preserving hormone. Mol Aspects Med 2005;26:203–219. 18. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB et al. Fall prevention with supplemental and active forms of vitamin D: A meta-analysis of randomised controlled trials. BMJ 2009;339:b3692. 19. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC et al. Effect of vitamin D on falls: A meta-analysis. JAMA 2004;291:1999–2006. 20. Vandervoort AA. Aging of the human neuromuscular system. Muscle Nerve 2002;25:17–25. 21. Bischoff-Ferrari HA, Borchers M, Gudat F et al. Vitamin D receptor expression in human muscle tissue decreases with age. J Bone Miner Res 2004;19:265–269. 22. Llewellyn DJ, Lang IA, Langa KM et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med 2010;170:1135–1141. 23. Annweiler C, Schott AM, Berrut G et al. Vitamin D and ageing: Neurological issues. Neuropsychobiology 2010;62:139–150. 24. Dhesi JK, Jackson SH, Bearne LM et al. Vitamin D supplementation improves neuromuscular function in older people who fall. Age Ageing 2004;33:589–595. 25. Buell JS, Dawson-Hughes B. Vitamin D and neurocognitive dysfunction: Preventing decline? Mol Aspects Med 2008;29:415–422. 26. Hanley DA, Cranney A, Jones G et al. Vitamin D in adult health and disease: A review and guideline statement from Osteoporosis Canada. CMAJ 2010;182:E610–E618. 27. Latham NK, Anderson CS, Reid IR. Effects of vitamin D supplementation on strength, physical performance, and falls in older persons: A systematic review. J Am Geriatr Soc 2003;51:1219–1226. 28. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998;52:377–384. 29. Altman DG, Schulz KF, Moher D et al. The revised CONSORT statement for reporting randomized trials: Explanation and elaboration. Ann Intern Med 2001;134:663–694. 30. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–1558. 31. Egger M, Davey Smith G, Altman D. Systematic Reviews in Health Care: Meta-Analysis in Context. London: BMJ Publishing Group, 2001. 32. Bischoff-Ferrari HA, Conzelmann M, Stahelin HB et al. Is fall prevention by vitamin D mediated by a change in postural or dynamic balance? Osteoporos Int 2006;17:656–663. 33. Bischoff HA, Stahelin HB, Dick W et al. Effects of vitamin D and calcium supplementation on falls: A randomized controlled trial. J Bone Miner Res 2003;18:343–351.

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34. Bunout D, Barrera G, Leiva L et al. Effects of vitamin D supplementation and exercise training on physical performance in Chilean vitamin D deficient elderly subjects. Exp Gerontol 2006;41:746–752. 35. Grady D, Halloran B, Cummings S et al. 1,25-Dihydroxyvitamin D3 and muscle strength in the elderly: A randomized controlled trial. J Clin Endocrinol Metab 1991;73:1111–1117. 36. Grieger JA, Nowson CA, Jarman HF et al. Multivitamin supplementation improves nutritional status and bone quality in aged care residents. Eur J Clin Nutr 2009;63:558–565. 37. Latham NK, Anderson CS, Lee A et al. A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: The Frailty Interventions Trial in Elderly Subjects (FITNESS). J Am Geriatr Soc 2003;51:291–299. 38. Moreira-Pfrimer LD, Pedrosa MA, Teixeira L et al. Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: A randomized doubleblind controlled trial. Ann Nutr Metab 2009;54:291–300. 39. Pfeifer M, Begerow B, Minne HW et al. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res 2000;15:1113–1118. 40. Pfeifer M, Begerow B, Minne HW et al. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int 2009;20:315–322. 41. Sato Y, Iwamoto J, Kanoko T et al. Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: A randomized controlled trial. Cerebrovasc Dis 2005;20:187–192. 42. Zhu K, Austin N, Devine A et al. A randomized controlled trial of the effects of vitamin D on muscle strength and mobility in older women with vitamin D insufficiency. J Am Geriatr Soc 2010;58:2063–2068. 43. Hewison M, Zehnder D, Bland R et al. 1alpha-Hydroxylase and the action of vitamin D. J Mol Endocrinol 2000;25:141–148. 44. Hewison M, Burke F, Evans KN et al. Extra-renal 25-hydroxyvitamin D31alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol 2007;103:316–321. 45. Eyles DW, Smith S, Kinobe R et al. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 2005;29:21– 30. 46. Visser M, Deeg DJ, Lips P. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): The Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 2003;88:5766–5772. 47. Sanders KM, Stuart AL, Williamson EJ et al. Annual high-dose oral vitamin D and falls and fractures in older women: A randomized controlled trial. JAMA 2010;303:1815–1822. 48. Kalyani RR, Stein B, Valiyil R et al. Vitamin D treatment for the prevention of falls in older adults: Systematic review and meta-analysis. J Am Geriatr Soc 2010;58:1299–1310. 49. Brunner RL, Cochrane B, Jackson RD et al. Calcium, vitamin D supplementation, and physical function in the Women’s Health Initiative. J Am Diet Assoc 2008;108:1472–1479.

Appendix 1 List of Retrieved Articles Excluded Based on Inclusion Criteria of Systematic Review Article

Binder EF. Implementing a structured exercise program for frail nursing home residents with dementia: Issue and challenges. J Aging Phys Act 1995;3:383–395. Bischoff-Ferrari HA, Orav EF, Dawson-Hughes B. Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: A 3-year randomized controlled trial. Arch Intern Med 2006;166:424–430. Broe KE, Cohen TC, Weinberg J, Bischoff-Ferrari HA, Holick MF, Kiel DP. A higher does of vitamin D reduces the risk of falls in nursing home residents: A randomized, multiple-dose study. J Am Geriatr Soc 2007;55:234–239.

Reason for Exclusion

Vitamin D supplementation in conjunction with exercise program Measures of gait, balance, or strength not assessed

Measures of gait, balance, or strength not assessed

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Appendix 1. (Contd.) Article

Brunner RL, Cochrane B, Jackson RD, Larson J, Lewis C, Limacher M, Rosal M, Shumaker S, Wallace R. Calcium, vitamin D supplementation, and physical function in the Women’s Health Initiative. J Am Diet Assoc 2008;108:1472–1479. Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S et al. Combined calcium and vitamin D3 supplementation in elderly women: Confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: The Decalyos II study. Osteoporos Int 2002;13:257–264. Corless D, Dawson E, Fraser F, Ellis M, Evans SJW, Perry JD, Reisner C, Silver CP, Beer M, Boucher BJ, Cohen RD. Do vitamin D supplements improve the physical capabilities of elderly hospital patients? Age Ageing 1985;14:76–84. Dawson-Hughes B, Harris SS, Krall Ea, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337:670–676. Dukas L, Bischoff HA, Lindpaintner LS, Schacht E, Birkner-Binder D, Damm TN, Thalmann B, Stahelin HB. Alfacalcidol reduces the number of fallers in a communitydwelling elderly population with a minimum calcium intake of more than 500 mg daily. J Am Geriatr Soc 2004;52:230–236. Flicker L, MacInnis RJ, Stein MS, Scherer SC, Mead KE, Nowson CA et al. Should older people in residential care receive vitamin D to prevent falls? Results of a randomized trial. J Am Geriatr Soc 2005;53:1881–1888. Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metab 2001;86:3618–3628. Gallagher JC, Rapuri PB, Smith LM. An age-related decrease in creatinine clearance is associated with an increase in number of falls in untreated women but not in women receiving calcitriol treatment. J Clin Endocrinol Metab 2007;92:51–58. Glerup H, Mikkelsen K, Poulsen L, Hass E, Overbeck S, Andersen H, Charles P, Eriksen EF. Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int 2000;66:419–424. Gloth FM, Smith CE, Hollis BW, Tobin JD. Functional improvement with vitamin D replenishment in a cohort of frail, vitamin D-deficient older people. J Am Geriatr Soc 1995;43:1269–1271. Graafmans WC, Ooms ME, Hofstee HMA, Bezemer PD, Bouter LM, Lips P. Falls in the elderly: A prospective study of risk factors and risk profiles. Am J Epidemiol 1996;143:1129–1136. Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): A randomized placebo-controlled trial. Lancet 2005;365:1621–1628. Harwood RH, Sahota O, Gaynor K, Masud T, Hosking DJ. A randomized, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study. Age Ageing 2004;33:45–51. Holm L, Olesen JL, Matsumoto K, Doi T, Mizuno M, Alsted TJ, Mackey AL, Schwarz P, Kjaer M. Protein-containing nutrient supplementation following strength training enhances the effect on muscle mass, strength, and bone formation in postmenopausal women. J Appl Physiol 2008;105:272–281. Honkanen R, Alhava E, Parviainen M, Talasniemi, Monkkonen R. The necessity and safety of calcium and vitamin D in the elderly. J Am Geriatr Soc 1990;38:862–866. Jackson RD, LaCroix AZ et al. Calcium plus vitamin D supplementation and the risk of fractures. New Engl J Med 2006;354:669–683. Johnson KR, Jobber J, Stonawski BJ. Prophylactic vitamin D in the elderly. Age Ageing 1980;9:121–127. Kiehn KA, Mahoney J, Jones AN, Hansen KE. Vitamin D supplement intake in elderly fallers. J Am Geriatr Soc 2009;57:176–177. Law M, Withers H, Morris J, Anderson F. Vitamin D supplementation and the prevention of fractures and falls: Results of a randomized trial in elderly people in residential accommodation. Age Ageing 2006;35:482–486. Prince RL, Austin N, Devine A, Dick IM, Bruce D, Zhu K. Effects of ergocalciferol added to calcium on the risk of falls in elderly high-risk women. Arch Intern Med 2008;168:103–108.


Sample included women younger than 60


Unvalidated method to quantify a summary measure of muscle strength Measures of gait, balance, or strength not assessed

Measures of gait, balance, or strength assessed at baseline only



Measures of gait, balance, or strength assessed at baseline only No control arm in study

Composite functional score did not include measures of balance, gait, or strength Measures of gait, balance, or strength assessed at baseline only Measures of gait, balance, or strength not assessed


Sample included women younger than 60

No control arm in study Measures of gait, balance, or strength not assessed Measures of gait, balance, or strength not performed on all subjects as per protocol Measures of gait, balance, or strength not assessed Measures of gait, balance, or strength not assessed


(Continued)

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Appendix 1. (Contd.) Article


Swanenburg J, de Bruin ED, Stauffacher M, Mulder T, Uebelhart D. Effects of exercise and nutrition on postural balance and risk of falling in elderly people with decreased bone mineral density: Randomized controlled trial pilot study. Clin Rehabil 2007;21:523–534. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: Randomized double blind controlled trial. BMJ 2003;326:469. Verhaar HJJ, Samson MM, Jansen PAF, de Vreede PL, Manten JW, Duursma SA. Muscle strength, functional mobility and vitamin D in older women. Aging Clin Exp Res 2000;12:455–460.

Exercise program randomized with all participants receiving the same calcium and vitamin D supplements


Open-label study

Effect of Vitamin D Supplementation on Muscle Strength

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