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. 2011 Jan;2(1):25–37. doi: 10.1177/2040622310381934

Effects of Vitamin D on Muscle Function and Performance: A Review of Evidence from Randomized Controlled Trials

Lars Rejnmark 1
PMCID: PMC3513873  PMID: 23251739

Abstract

Vitamin D insufficiency is frequent in the general population. Meta-analyses of randomized controlled trials (RCTs) have shown a decreased risk of falls in elderly treated with vitamin D supplements, which may be due to an improved neuromuscular function in vitamin D-replete subjects. In most observational studies, vitamin D status correlates positively with muscle strength and postural stability. However, as physical activity is associated with vitamin D status as well as muscle strength, effects of vitamin D status on muscular health can only be assessed properly in RCTs. A systematic search was performed and 16 RCTs on the effects of treatment with vitamin D on muscle function were identified. All except one of the studies were performed in subjects above 50 years of age. Baseline 25-hydroxyvitmin D (25OHD) levels were below 50 nmol/l in 11 studies. Plasma 25OHD levels increased significantly in all studies. In seven studies, a beneficial effect of vitamin D treatment was documented on muscle strength of the lower legs, body sway, and/or physical performance. Identified studies were heterogeneous with regard to most aspects including indices measured. No obvious characteristics delineated studies showing beneficial effects from studies showing no effects. Only a few investigators reported the statistical power of measurements performed. In conclusion, evidence from RCTs do support an effect of vitamin D supplements on muscle strength and function in the elderly, but more studies showing a lack of an effect have been published than studies showing beneficial effects. There is a major lack of data on possible effects in younger subjects.

Keywords: elderly, muscle strength, vitamin D

Introduction

For many years, vitamin D has been known to be of importance to musculoskeletal health [Pfeifer et al. 2002]. It is well known that severe deficiency causes rickets (in children) and osteomalacia (‘softening of the bones’) in adults. Symptoms include paresthesia in hands and feet as well as aching muscles and bones [Ahmed et al. 2009; Pfeifer et al. 2002; Glerup and Eriksen, 1999]. Findings include muscle weakness with particularly proximal myopathy causing difficulty getting up from a chair without using arms and by walking on stairs [Schott and Wills, 1976; Skaria et al. 1975]. Gait disturbance occur and gait is often characterized as waddling (‘penguin gait’) [Glerup et al. 2000; Boland, 1986; Skaria et al. 1975]. The clinical feature of the myopathy associated with severe vitamin D deficiency is supported by findings from in vivo and in vitro experimental studies showing histological and electrophysiological changes in severe vitamin D deficiency [Sato et al. 2005; Boland, 1986; Sorensen et al. 1979; Skaria et al. 1975]. The vitamin D receptor (VDR) is expressed in the cell nuclei of muscle cells [Bischoff-Ferrari et al. 2004a; Bischoff et al. 2001; Simpson et al. 1985] and vitamin D has been shown to affect muscle cell contractility [Marcinkowska, 2001; Bellido and Boland, 1991; Rodman and Baker, 1978]. The number of VDRs decreases with age, which supposedly is a contributing factor to reduced muscle strength in the elderly [Bischoff-Ferrari et al. 2004a]. In addition to a direct effect of vitamin D on muscle cells, vitamin D deficiency causes secondary hyperparathyroidism (SHPT) which may also impair muscle function [Baczynski et al. 1985].

Vitamin D is either ingested from food or synthesized in the skin during sun exposure. In most subjects, sun exposure is the primary determinant of vitamin D status, accounting for 80–90% of the vitamin D body stores. Cholecalciferol (vitamin D3) is synthesized in the skin and found in fatty fish and mammals, whereas ergocalciferol (vitamin D2) comes from yeasts and plants. Vitamin D supplements may contain either vitamin D2 or D3. Previously, the two vitamin D metabolites were considered to have an equal potency, but recent studies have suggested that vitamin D2 may be inferior to vitamin D3 in the treatment of vitamin D insufficiency [Romagnoli et al. 2008]. Vitamin D2 and D3 are both hydroxylated primarily in the liver to 25-hydroxyvitamin D (25OHD) and subsequently in the kidneys (and different peripheral cells) to become the active vitamin D metabolite, 1,25-dihydroxyvitamin D (calcitriol), which acts on the VDR [Hewison et al. 2000].

Vitamin D status is usually assessed by measuring plasma 25OHD levels. Plasma 25OHD levels below 50 nmol/l are considered as a state of insufficiency, although an increasing number of studies suggest that levels above 80 nmol/l are needed to ensure an optimal vitamin D status [Dawson-Hughes et al. 2005]. Vitamin D deficiency is defined as plasma 25OHD levels below 25 nmol/l, and levels below 12 nmol/l are considered as a state of severe deficiency which may cause frank osteomalacia and severe proximal myopathy.

In vitamin D insufficiency, muscle function and physical function may be impaired before clinical or biochemical signs of bone disease are evident [Glerup et al. 2000]. An increased risk of falls in elderly subjects with low vitamin D levels have been documented in several studies and randomized controlled trials (RCTs), and meta-analyses of RCTs have shown a reduced risk of falls in elderly treated with vitamin D supplements [Bischoff-Ferrari et al. 2009; Jackson et al. 2007; Bischoff et al. 2003]. Most likely, this is due to an improved neuromuscular function in response to vitamin D supplementation. Similarly, associations between vitamin D status and muscle strength, body sway and physical performance have been investigated in a large number of cohort and cross-sectional studies with most [Kuchuk et al. 2009; Stewart et al. 2009; Ward et al. 2009; Houston et al. 2007; Rinaldi et al. 2007; Wicherts et al. 2007; Bischoff-Ferrari et al. 2004b; Dhesi et al. 2002; Bischoff et al. 2000, 1999; Mowe et al. 1999; Skaria et al. 1975], but not all [Annweiler et al. 2009a, 2009b; Verreault et al. 2002], studies showing the beneficial effect of vitamin D status on measured indices. However, interpretation of results from observational studies is difficult, as plasma 25OHD levels, physical activity and muscle strength are closely interrelated. In several studies, physical activity has been shown to correlate positively with vitamin D status which most likely is due to the fact that physically active subjects spend more time outdoors in the sun and accordingly have a higher endogenous vitamin D synthesis than physically inactive subjects [Scragg and Camargo, 2008; Scragg et al. 1995]. In addition, physical activity improves muscle strength. Although most observational studies have adjusted statistically for potential interactions of physical activity and vitamin D status on muscular strength, residual confounding may exist and accordingly results from RCTs are imperative in order to draw valid conclusions on the effects of vitamin D status on muscle function.

The aim of the present paper is to review systematically the current state of knowledge on the effects of vitamin D on muscle strength and performance, based on results from individual RCTs.

Methods

By systematically searching the electronic databases MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews, studies published in the English language up to March 2010 on vitamin D, muscle strength, function and performance were identified. This was supplemented by searching the reference lists of the retrieved articles, textbooks and reviews.

Selection criteria

Only randomized trials of vitamin D supplementation in terms of either ergo- or cholecalciferol compared with placebo or with active comparators were included. Studies on the effects of treatment with active vitamin D (alfacalcidol, calcitriol) were excluded. Data on quality of life (QoL) from questionnaires were included if the study aim was to assess the effects on musculoskeletal function, but the search did not include data from studies including questionnaires on QoL without assessing muscle function.

Types of outcome measures

Data on the place of study and participant characteristics were collected (age, sex, residential status in terms of community-dwelling or patients and the condition to be treated) together with the following:

  • treatment regime (type and dose of vitamin D administrated, concomitant administration of calcium and duration of treatment);

  • type of outcome measures used in the individual studies, including the methods used to assess muscle strength, body sway, physical performance and questionnaires used;

  • effects of vitamin D treatment compared with placebo/active comparator on the individual outcome measures;

  • plasma 25OHD and parathyroid hormone (PTH) levels at baseline and end of study (when reported).

Results

A total of 18 RCTs were identified [Janssen et al. 2010; Lips et al. 2010; Witham et al. 2010; Kukuljan et al. 2009; Moreira-Pfrimer et al. 2009; Brunner et al. 2008; Bunout et al. 2006; Hajj Fuleihan et al. 2006; Sato et al. 2005; Dhesi et al. 2004; Bischoff et al. 2003; Kenny et al. 2003; Latham et al. 2003; Pfeifer et al. 2009, 2000; Cordless et al. 1985; Johnson et al. 1980], among which two were omitted from further analysis as one of the papers reported duplicate data [Bischoff-Ferrari et al. 2006] and the other paper lacked detailed information on muscle measurements preformed [Johnson et al. 1980]. A summary of included studies is presented in Table 1. Only 1 of the 16 studies was not performed as a double-blinded trial [Lips et al. 2010]. The 16 RCTs included a total of 35,283 subjects. The trial from the Women's Health Initiative (WHI) study was substantially larger than any of the other trials, reporting physical functioning questionnaires data on 33,067 women, and clinical physical function measures in a subsample of 3137 women [Brunner et al. 2008]. The other 15 studies included a total of 2216 subjects with 65 to 363 subjects included in each of the individual trials (Table 1). All except one study [Hajj Fuleihan et al. 2006] included only subjects aged >50 years, and the mean age of included subjects was ≥74 years in 13 of the studies (Table 1). Solely females were included in five studies [Janssen et al. 2010; Brunner et al. 2008; Sato et al. 2005; Bischoff et al. 2003; Pfeifer et al. 2000], whereas two studies included only males [Kukuljan et al. 2009; Kenny et al. 2003]. Eight studies had frailty as a criteria for inclusion, as only subjects from geriatric care units [Janssen et al. 2010; Moreira-Pfrimer et al. 2009; Bischoff et al. 2003; Latham et al. 2003; Cordless et al. 1985], subjects with poststroke hemiplegia [Sato et al. 2005], heart failure [Witham et al. 2010] or a history of falls [Dhesi et al. 2004] were included (Table 1).

Table 1.

Randomized controlled trials on effects of vitamin D on muscle function.

Reference Study population; age; mean (range); place of study Intervention; duration of treatment; design Effects on plasma 250HD and PTH levels in the control (C) and vitamin D intervention (I) group Effects on muscle function
Start of study End of study
Cord Less et al. [1985] 65 male and female in-patients from a geriatric ward. All with P-250HD <40 nmol/l; age 82 y; England Daily oral 9000 IU of D2 vs. identical placebo tablets; 6 months; double-blind design P-250HD: C: 17 nmol/l I: 18 nmol/l P-250HD: C: 15 nmol/l I: 120 nmol/l# Using Northwick Park ADL system, the intervention did not affect ‘Muscle strength score’ or ‘activity of daily living score’. Neither did treatment affect ‘mental assessment scores’ as assessed by a short questionnaire followed by a simple practical test of cognitive functions.
P-PTH: NA
Pfeifer et al. [2000] 148 healthy free-living women with P-25OHD <50 nmol/l; age 74 (70–86) y; Germany Daily oral 800 IU D3 + 1200 mg calcium vs. 1200 mg calcium alone; 2 months; double-blind design P-250HD: C: 25 nmol/l I: 26 nmol/l ‘P-250HD: C: 43 nmol/l I: 67 nmol/l# Compared with calcium alone, treatment with calcium plus vitamin D significantly reduced body sway (measured by the use of a sway meter).
P-PTH: C: 6.1 pmol/l I: 6.1 pmol/l P-PTH: C: 5.2 pmol/l I: 4.4 pmol/l#
Bischoff et al. [2003] 122 institutionalized women from a long-stay geriatric care unit; age 85 (63–99) y; Switzerland Daily oral 800 IU D3 + 1200 mg calcium vs. 1200 mg calcium alone; 3 months; double-blind design P-250HD: C: 29 nmol/l I: 31 nmol/l P-250HD: C: 29 nmol/l I: 66 nmol/l# No effects on individual measurement of isometric muscle strength at knee flexion and extension, grip strength or the TUG test. Combining the four individual measures into an overall ‘musculoskeletal function index’ showed significantly improvement in the vitamin D + calcium group compared with calcium alone.
P-PTH: C: 3.7 pmol/l I: 3.9 pmol/l P-PTH:C: 3.7 pmol/l I: 2.8 pmol/l#
Kenny et al. [2003] 65 healthy, community-dwelling males; age: 76 (65–87) y; Connecticut, USA Daily oral 1000 IU D3 + 500 mg calcium vs. 500 mg calcium alone; 6 months; double-blind design P-250HD: C: 59 nmol/l I: 65 nmol/l P-250HD: C: 57 nmol/l I: 87 nmol/l# No effect on leg extension strength, handgrip strength (dynamometer), physical performance (including ability to rise from a chair, static balance, 6-foot walk time and TUG test), Physical Activity Scale for the Elderly (PASE) questionnaire, or the Medical Outcome Survey Short-form 8.
P-PTH: C: 6.6 pmol/l I: 6.4- pmol/l P-PTH: C: 6.4 pmol/l I: 4.0 pmol/l ¤)
Latham et al. [2003] 24–3 frail males and females (53%) admitted to a geriatric rehabilitation unit (inpatient or day ward); age: 79 (77–81) y; New Zealand and Australia Single oral dose of 300,000 IU D2 vs. placebo tablets; 6 months follow up; double-blind design P-250HD: C: 48 nmol/l I: 38 nmol/l P-250HD: C: 48 nmol/l I: 60 nmol/l# No effects on isometric knee extensor strength (dynamometer), the Berg Balance Test, TUG test, the time taken to walk 4- meters or the Short Form 36-item [SF36] questionnaire. Neither did treatment with vitamin D alter any of the physical performance measures in the subgroup of subjects with baseline 250HD levels <30 nmol/l.
P-PTH: NA
Dhesi et al. [2004] 139 males and females (75%) with a history of falls and P-250HD <30 nmol/l; age: 77 y (All > 65 y); England Single intramuscular injection of 600,000 IU D2 vs. placebo injection; 6 months follow-up; double-blind design P-250HD: C: 25 nmol/l I: 27 nmol/l P-250HD: C: 27 nmol/l I: 44 nmol/l# Compared with placebo, vitamin D improved significantly postural sway (bipedal stance with eyes open, on a platform), aggregate functional performance time (the time taken to perform four common activities of daily living), and four-choice reaction time. No effect on maximal voluntary isometric quadriceps strength (using a strain gauge system) or QoL as assessed by SF35 questionnaire.
P-PTH: C: 6.5 pmol/l I: 5.7 pmol/l P-PTH: C: 6.6 pmol/l I: 5.5 pmol/l
Sato et al. [2005] 96 women with post-stroke hemiplegia; age 74 y; Japan Daily oral 1000 IU D2 vs. placebo; 24 months; double-blind design P-250HD: C: 55 nmol/l I: 55 nmol/l P-250HD: C: 50 nmol/l I: 81 nmol/l# Muscle strength was evaluated on the gluteus maximus and iliopsoas muscles on the nonhemiplegic side by a physical therapist using the British Medical Research Council scale. After 2 years of treatment, muscle strength on intact side had improved significantly in the vitamin D2 group (57 ± 41%) compared with the changes in the placebo group (-28 ± 12%; p < 0.01). Muscle biopsies showed a significantly increased diameter of Type II fibres, and an increased percentages of Type II fibres.
P-PTH: C: 2.0 pmol/l I: 2.0 pmol/l P-PTH: C: 2.4 pmol/l I: 2.4 pmol/l
Hajj Fuleihan et al. [2006] 363 healthy boys and girls (49%) Recruited from 4 schools in the greater Beirut area; age 13 (10–17) y; Lebanon Weekly oral 1400 IU D3 vs. weekly oral 14000 IU D3 vs. placebo; 12 months; double-blind design P-250HD: C: 35 nmol/l llow: 35 nmol/l lHigh: 35 nmol/l PTH: NA P-250HD: C: 40 nmol/l llow: 43 nmol/l lHigh: 95 nmol/l# Compared with placebo, both doses of vitamin D caused a significant increase in lean tissue mass In pre-but not in postmenarcheal girls. No dose—response effect. No effect on grip strength, as measured by a pneumatic squeeze dynamometer. In boys, there was no consistent positive effect of vitamin D.
Bunout et al. [2006] 96 elderly healthy free-living males and females (90%) with P-250HD <40 nmol/l; age: 77 y; Chile Daily oral 400 IU D3 + 800 mg calcium vs. 800 mg calcium alone; 9 months; double-blind design, full factorial design, i.e. in addition to supplements subjects were randomized to either physical training or no training. P-250HD: C: 33 nmol/l I: 31 nmol/l P-250HD: C: 36 nmol/l I: 65 nmol/l# TUG, 12 minute gait speed, and body sway (using a computerized posturograph) improved significantly in the vitamin D + calcium group compared with the calcium alone group. No effect on handgrip (dynamometer) or isometric quadriceps maximum voluntary strength, as assessed by using a quadriceps table.
P-PTH: did not change in any of the studied groups
Brunner et al. [2008] 33,067 free-living women; age 62 [50–79] y; USA Daily oral 400 IU D3 + 1000 mg calcium vs. placebo; 7 y follow up; double-blind design, sub-study within the Women's health initiative (WHI) study. Women were additionally randomized to hormone therapy and dietary modification trials P-250HD: NA Physical functioning was assessed in questionnaires incl. the SF36, showing no effects. A random sub-sample (n = 3137) of subjects had three objective physical function measures made at WHI baseline and 2- and 5-years after calcium/vitamin D trial enrolments. No effects of treatment were found on grip strength (dynamometer), chair—stand test, or 6-m timed walk test.
Pfeifer et al. [2009] 242 elderly community-dwelling males and females (75%) with P-250HD <78 nmol/l; age: 77 (all > 70) y; Germany and Austria Daily oral 800 IU D3 + 1000 mg calcium vs. 1000 mg calcium alone; 12 months followed by a treatment-free but still blinded 8 months observation period; double-blind design P-250HD: C: 54 nmol/l I: 55 nmol/l P-250HD: C: 57 nmol/l I: 84 nmol/l# Compared with calcium alone, calcium plus vitamin D increased significantly quadriceps strength by 8% (using a dynamometer), and decreased significantly TUG by 11%. These changes remained significant at months 20. In addition at months 20, body sway (using a sway meter) was decreased significantly by 28% in the calcium + vitamin D group compared with the calcium alone group.
P-PTH: C: 5.8 pmol/l I: 5.3 pmol/l P-PTH: C: 4.3 pmol/l I: 3.9 pmol/l ¤)
Kukuljan et al. [2009] 180 healthy community-dwelling White men; age: 61 (50–79) y; Australia Daily fortified milk with 800 IU D3 + 1000 mg calcium vs. no consumption of fortified milk; 18 months; randomized but not blinded, full factorial design, i.e. in addition to supplements subjects were randomized to either physical training or no training P-250HD: C: 85 nmol/l I: 87 nmol/l P-250HD: C: 75 nmol/l I: 97 nmol/l# No effects on muscle strength (assessed as leg press, latissimus dorsi pull down and bench press) or postural sway (using a sway meter).
P-PTH: C: 2.9 pmol/l I: 3.0 pmol/l P-PTH: did not change significantly
Moreira-Pfrimer et al. [2009] 56 males and females (79%) living in long-stay geriatric care units; age 78 (62–94) y; Brazil Calcium 1000 mg/d + oral D3 150,000 IU once a month during the first 2 months, followed by 90,000 IU D3 once a month for the next 4- months vs. calcium 1000 mg/d; 6 months; double-blind design P-250HD: C: 40 nmol/l I: 46 nmol/l P-250HD: C: 52 nmol/l I: 87 nmol/l# Vitamin D caused a significant improvement in maximal isometric strength of hip flexors and knee extensors (dynamometer).
P-PTH: C: 5.0 pmol/l I: 5.3 pmol/l P-PTH: C: 5.2 pmol/l I: 4.6 pmol/l
Witham et al. [2010] 105 males and females (34%) with systolic heart failure and P-250HD <50 nmol/l; age 79 (all > 70) y; Scotland Oral 100,000 IU D2 at baseline and 10 weeks later vs. similar placebo; 5 months follow-up; double-blind design P-250HD: C: 24 nmol/l I: 21 nmol/l P-250HD: C: 25 nmol/l I: 40 nmol/l# No effects on 6-minute walk distance, TUG test, or Functional Limitations Profile. QoL as measured by the Minnesota Living With Heart Failure score worsened slightly, but significant in the treatment-compared with the placebo-group.
P-PTH: C: 8.5 pmol/l I: 8.7 pmol/l P-PTH: C: 8.5 pmol/l I: 8.1 pmol/l
Lips et al. [2010] 226 ambulatory males and females with P-250HD between 15 and 50 nmol/l; age: 78 (all ≥ 70) y; medical centres in North America and Europe Weekly oral 8400 IU D3 vs. placebo; 4 months; double-blind design P-250HD: C: 35 nmol/l I: 34 nmol/l P-250HD: C: 35 nmol/l I: 66 nmol/l# No effects of treatment on mediolateral body sway with eyes open (assessed using an AccuSwayPLUS platform], gait speed test, or on a short physical performance battery (combined measures of balance, gait speed, and ability to rise from a chair). No significant treatment differences in mediolateral sway were seen in either of two prespecified subgroups on the basis of the baseline 25(OH)D concentration (≤15 or > 15 ng/ml).
P-PTH: C: 6.2 pmol/l I: 6.4 pmol/l P-PTH: C: 6.7 pmol/l I: 6.1 pmol/l#
Janssen et al. [2010] 70 female geriatric outpatients with P-250HD between 20 and 50 nmol/l; age: 81 (all > 65] y; The Netherlands Daily ora 400 IU D3 + 500 mg calcium vs. 500 mg calcium; 6 months; double-blind design P-250HD: C: 34 nmol/l I: 33 nmol/l P-250HD: C: 42 nmol/l I: 77 nmol/l# No effects on handgrip strength (dynamometer), isometric knee extension strength (dynamometry), explosive leg extension power (Nottingham Power Rig), TUG test, maximum walking distance achieved in 2 minutes, or habitual physical activity as measured with a physical activity questionnaire for the elderly.
P-PTH: C: 9.1 pmol/l I: 10.6 pmol/l P-PTH: C: 7.4 pmol/l I: 7.1 pmol/l
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p < 0.05 between treatment groups.

P-250HD, plasma 25-hydroxyvitamin D; P-PTH, plasma parathyroid hormone; TUG, timed up-and-go test; QoL, quality of life.

Type and duration of interventions

In most studies, vitamin D3 has been administrated orally as either a daily [Janssen et al. 2010; Kukuljan et al. 2009; Pfeifer et al. 2009, 2000; Brunner et al. 2008; Bunout et al. 2006; Bischoff et al. 2003; Kenny et al. 2003], weekly [Lips et al. 2010; Hajj Fuleihan et al. 2006] or monthly [Moreira-Pfrimer et al. 2009] dose. In most studies, an average daily dose of between 400 and 1200 IU of vitamin D3 was studied, whereas two studies used substantially higher average doses administrated either weekly (2000 IU/day) [Hajj Fuleihan et al. 2006] or monthly (3700 IU/day) [Moreira-Pfrimer et al. 2009]. In five studies, vitamin D2 has been administrated as either a single intramuscular [Dhesi et al. 2004] or oral [Latham et al. 2003] dose, as two doses administrated 10 weeks apart [Witham et al. 2010], or as a daily oral dose [Sato et al. 2005; Cordless et al. 1985]. As shown in Table 1, the doses of vitamin D2 used have varied widely. In nine studies, vitamin D3 has been administrated in combination with a daily calcium supplement [Janssen et al. 2010; Kukuljan et al. 2009; Moreira-Pfrimer et al. 2009; Pfeifer et al. 2009, 2000; Brunner et al. 2008; Bunout et al. 2006; Bischoff et al. 2003; Kenny et al. 2003] and in these studies calcium alone (without vitamin D) has been used as a comparator (Table 1).

In the WHI study, follow up was performed after an average of 7.1 years [Brunner et al. 2008], whereas time to follow up has varied from 2 to 24 (average 8) months in the other 15 studies (Table 1).

Effects of interventions on plasma 25OHD and PTH levels

In all but one study [Brunner et al. 2008], the effect of treatment on plasma 25OHD levels has been reported, showing a significant increase in 25OHD levels in vitamin D treated subjects compared with controls (Table 1).

Baseline plasma 25OHD levels were below 50 nmol/l in 11 of the included studies. In 13 studies, the effects of treatment on plasma PTH levels was reported showing either significantly decreased levels [Lips et al. 2010; Pfeifer et al. 2009, 2000; Bischoff et al. 2003; Kenny et al. 2003] or no effects [Janssen et al. 2010; Lips et al. 2010; Witham et al. 2010; Kukuljan et al. 2009; Moreira-Pfrimer et al. 2009; Bunout et al. 2006; Sato et al. 2005; Dhesi et al. 2004] compared with the controls (Table 1). Vitamin D3 has been co-administrated with calcium in four of the five studies showing decreased PTH levels [Pfeifer et al. 2009, 2000; Bischoff et al. 2003; Kenny et al. 2003], as well as in four of the studies showing no effects on PTH levels [Janssen et al. 2010; Kukuljan et al. 2009; Moreira-Pfrimer et al. 2009; Bunout et al. 2006]. No apparent differences exist between studies showing or not showing effects on plasma PTH levels regarding dose of vitamin D administrated or baseline plasma 25OHD levels (Table 1). However, none of the studies using vitamin D2 showed effects on plasma PTH levels [Witham et al. 2010; Sato et al. 2005; Dhesi et al. 2004].

Effects on muscle function

Overall, seven studies showed a positive effect of vitamin D treatment on muscle strength, postural sway and/or physical performance [Moreira-Pfrimer et al. 2009; Pfeifer et al. 2009, 2000; Bunout et al. 2006; Sato et al. 2005; Dhesi et al. 2004; Bischoff et al. 2003], whereas nine studies found no evidence of effects on measured indices [Janssen et al. 2010; Lips et al. 2010; Witham et al. 2010; Kukuljan et al. 2009; Brunner et al. 2008; Hajj Fuleihan et al. 2006; Kenny et al. 2003; Latham et al. 2003; Cordless et al. 1985].

Effect on muscle strength

Effects of vitamin D on muscle strength was evaluated in 12 studies [Janssen et al. 2010; Kukuljan et al. 2009; Moreira-Pfrimer et al. 2009; Pfeifer et al. 2009; Brunner et al. 2008; Bunout et al. 2006; Hajj Fuleihan et al. 2006; Sato et al. 2005; Dhesi et al. 2004; Bischoff et al. 2003; Kenny et al. 2003; Latham et al. 2003]. In most studies, a dynamometer/strain gauge system was used to measure maximal voluntary isometric muscle strength [Janssen et al. 2010; Moreira-Pfrimer et al. 2009; Pfeifer et al. 2009; Brunner et al. 2008; Bunout et al. 2006; Fuleihan et al. 2006; Dhesi et al. 2004; Bischoff et al. 2003; Hajj Kenny et al. 2003; Latham et al. 2003].

Lower legs isometric muscle strength, as assessed by using a strain gauge system, was evaluated in eight studies [Janssen et al. 2010; Moreira-Pfrimer et al. 2009; Pfeifer et al. 2009; Bunout et al. 2006; Dhesi et al. 2004; Bischoff et al. 2003; Kenny et al. 2003; Latham et al. 2003]. Two studies showed an improved isometric muscle strength in response to treatment [Moreira-Pfrimer et al. 2009; Pfeifer et al. 2009]. Accordingly, in response to 6 months of treatment with 800 IU/day vitamin D3, Pfeifer and colleagues found significantly increased quadriceps strength compared with placebo [Pfeifer et al. 2009]. Similarly, Moreira-Pfrimer and colleagues found significantly improved maximal isometric strength of hip flexors and knee extensors in vitamin D3-treated subjects compared with placebo [Moreira-Pfrimer et al. 2009].

In addition to using a strain gauge system, effects of vitamin D treatment have been evaluated in a Japanese study in terms of a physical therapist (blinded to treatment allocation) assessing muscle strength using the British Medical Research Council scale. The study included women with poststroke hemiplegia and showed that compared with placebo, 2 years of treatment with 1000 IU/day vitamin D2 caused a significantly improved strength of the gluteus maximus and iliopsoas muscles on the intact side [Sato et al. 2005].

Effects of vitamin D treatment on hand grip strength have been evaluated in five studies, none of them showing significant effects [Janssen et al. 2010; Brunner et al. 2008; Bunout et al. 2006; Hajj Fuleihan et al. 2006; Kenny et al. 2003].

As shown in Table 1, no obvious differences exist between the studies showing or not showing effects in terms of characteristics of included subjects or effects of treatment on plasma 25OHD or PTH levels.

Body sway

Effects of vitamin D on postural balance have been evaluated in eight RCTs [Lips et al. 2010; Kukuljan et al. 2009; Pfeifer et al. 2009, 2000; Bunout et al. 2006; Dhesi et al. 2004; Kenny et al. 2003; Latham et al. 2003]. In four studies treatment with vitamin D decreased body sway as assessed by the use of either a sway meter [Pfeifer et al. 2009, 2000] or a balance platform [Bunout et al. 2006; Dhesi et al. 2004], whereas no effect was found in another four studies assessing postural balance by the use of either a sway meter [Kukuljan et al. 2009], a balance platform [Lips et al. 2010], single leg stance (seconds) [Kenny et al. 2003], or Berg Balance Test [Latham et al. 2003]. All of the four studies showing an effect included only subjects who had low vitamin D levels at baseline, whereas only one of the three studies showing no effect had low plasma 25OHD levels as inclusion criteria. In terms of other characteristics, no obvious differences exist between studies showing or not showing an effect (Table 1).

Physical performance

Effects on physical performance have been assessed using a variety of different measures (Table 1), including the timed up-and-go (TUG) test [Janssen et al. 2010; Witham et al. 2010; Pfeifer et al. 2009; Bunout et al. 2006; Bischoff et al. 2003; Kenny et al. 2003; Latham et al. 2003], gait speed tests [Janssen et al. 2010; Lips et al. 2010; Witham et al. 2010; Brunner et al. 2008; Bunout et al. 2006; Kenny et al. 2003; Latham et al. 2003], chair—stand tests [Brunner et al. 2008; Kenny et al. 2003], as well as by the use of aggregated measures of physical abilities [Lips et al. 2010; Witham et al. 2010; Dhesi et al. 2004; Bischoff et al. 2003; Kenny et al. 2003; Cordless et al. 1985] and different questionnaires [Witham et al. 2010; Brunner et al. 2008; Dhesi et al. 2004; Kenny et al. 2003; Latham et al. 2003; Cordless et al. 1985].

In seven studies, the effect of vitamin D on the TUG test has been investigated [Janssen et al. 2010; Witham et al. 2010; Pfeifer et al. 2009; Bunout et al. 2006; Bischoff et al. 2003; Kenny et al. 2003; Latham et al. 2003]. In two studies, a beneficial effect was shown [Pfeifer et al. 2009; Bunout et al. 2006]. Both studies include only study subjects with low vitamin D levels at baseline, whereas low baseline vitamin D levels were a predefined criteria for inclusion in two [Janssen et al. 2010; Witham et al. 2010] of the five studies showing no effect. In two studies, no effect of vitamin D was shown on the ability to rise from a chair (chair—stand test) [Brunner et al. 2008; Kenny et al. 2003].

Whether vitamin D affects gait speed has been tested in seven trials [Lips et al. 2010; Janssen et al. 2010; Witham et al. 2010; Brunner et al. 2008; Bunout et al. 2006; Kenny et al. 2003; Latham et al. 2003] assessing time taken to walk either 6 feet [Kenny et al. 2003], 4 meters [Lips et al. 2010; Latham et al. 2003] or 6 meters [Brunner et al. 2008]. In addition, the maximum walking distance achieved in either 2 [Janssen et al. 2010], 6 [Brunner et al. 2008] or 12 minutes [Bunout et al. 2006] have been measured. Only one of the studies showed a significant effect of vitamin D treatment. Accordingly, in a group of 96 elderly, community-dwelling males and females with plasma 25OHD <40 nmol/l, Bunout and colleagues found an increased 12-minute gait speed in response to 9 months of treatment with a daily dose of 400 IU vitamin D3 + 800 mg calcium compared with 800 mg calcium alone (Table 1) [Bunout et al. 2006].

As shown in Table 1, the effects of vitamin D on physical performance have been investigated in terms of different aggregated measures of physical abilities in six studies [Lips et al. 2010; Witham et al. 2010; Dhesi et al. 2004; Bischoff et al. 2003; Kenny et al. 2003; Cordless et al. 1985]. In two studies, a beneficial effect of vitamin D was shown [Dhesi et al. 2004; Bischoff et al. 2003]. Both studies included rather frail study subjects, i.e. in the study by Bischoff and colleagues only institutionalized elderly women (mean age 85 years) from a long-stay geriatric care unit participated [Bischoff et al. 2003], and in the study by Dhesi and colleagues only subjects with a history of falls and plasma 25OHD levels < 30 nmol/l were included [Dhesi et al. 2004]. In the study by Bischoff and colleagues no significant effects of individual muscle measurements were shown, but a positive effect was demonstrated by combining four individual measures of muscle strength (isometric muscle strength at knee flexion and extension, grip strength and the TUG test) into an overall musculoskeletal function index [Bischoff et al. 2003]. Similarly, Dhesi and colleagues showed no effect on individual measures of muscle strength but a beneficial effect of vitamin D was shown by combining the time taken to perform four common activities of daily living (50-foot walk, rising from a 42-cm high chair and walking 50 feet, ascent and descent of 13 steps) into an aggregate functional performance time [Dhesi et al. 2004]. In the studies showing no effects, different measures of physical performance have been combined (Table 1). So far, all published studies have used their ‘own’ combined measures of physical performance, i.e. no two studies have assessed the same measure. No effects of vitamin D treatment on musculoskeletal function have been demonstrated by the use of different types of questionnaires [Witham et al. 2010; Brunner et al. 2008; Dhesi et al. 2004; Kenny et al. 2003; Latham et al. 2003; Cordless et al. 1985], including the Short Form 36 (SF36) questionnaire [Brunner et al. 2008; Dhesi et al. 2004; Latham et al. 2003].

Discussion

For the present review, 16 RCTs on the effects of vitamin D supplements on muscle function were identified. Except for one study, all studies included solely subjects older than 50 years of age indicating a major lack of data on the effects of vitamin D on muscle function in younger subjects.

In general, the studies identified all showed significant effects of vitamin D supplementation on plasma 25OHD levels, whereas only 5 of 13 studies reported decreased plasma PTH levels in response to treatment. A little less than half of the studies showed beneficial effects of vitamin D treatment on muscle function in terms of an improved muscle strength [Moreira-Pfrimer et al. 2009; Pfeifer et al. 2009; Sato et al. 2005], a reduced body sway [Pfeifer et al. 2009, 2000; Bunout et al. 2006; Dhesi et al. 2004], an improved TUG test [Pfeifer et al. 2009; Bunout et al. 2006], an increased 12-minute gait speed [Bunout et al. 2006] or an improved aggregated measure of physical abilities [Dhesi et al. 2004; Bischoff et al. 2003]. Accordingly, the findings from observational studies on the effects of vitamin D on muscle function is to a certain degree supported by the finding from RCTs, although the beneficial effects of vitamin D are less consistently present. In contrast to the findings from observational studies on beneficial effects of vitamin D status on grip strength in adolescent girls [Foo et al. 2009] and postmenopausal women [Stewart et al. 2009], no RCTs have shown effects of vitamin D supplements on grip strength. This agrees with the notion that vitamin D primarily affects the proximal muscles causing proximal myopathy in the state of severe deficiency. As all studies showing beneficial effects of vitamin D supplements on body sway [Pfeifer et al. 2009, 2000; Bunout et al. 2006; Dhesi et al. 2004] and the TUG test [Pfeifer et al. 2009; Bunout et al. 2006] had low baseline plasma 25OHD levels as a predefined criteria for inclusion, it seems likely that a beneficial effect is more prone to be shown in the setting of low vitamin D levels. However, it should be noted that several of the studies with a lack of an effect also included solely study subjects with plasma 25OHD levels below a certain limit [Kukuljan et al. 2009; Brunner et al. 2008; Hajj Fuleihan et al. 2006; Kenny et al. 2003; Latham et al. 2003], making it difficult to draw any definite conclusions on this matter (Table 1).

Overall, no major differences are apparent between the seven studies showing a beneficial effect and the nine studies with a lack of an effect of vitamin D treatment on measured indices (Table 1). Nevertheless, conclusions should only be drawn with caution on whether the characteristics of studied subjects or dose of vitamin D used are of importance, as the studies identified were heterogeneous with regard to most aspects. Different outcome measures have been reported by different investigators and even in the case of measurements of similar characteristics, different methods have been applied making it difficult to compare studies directly. Moreover, although measured indices have been investigated in the setting of RCTs, the effects on muscle function have been investigated as secondary endpoints in most studies and only few investigators have reported sample size calculations of measurements performed [Lips et al. 2010]. It cannot be ruled out that the lack of effect in some of the studies may be due to a low statistical power (Type II error).

Several in vivo and in vitro experimental studies have shown physiological, histological and electrophysiological changes in severe vitamin D deficiency, supporting an effect of vitamin D on muscle health. Binding of vitamin D to its receptors stimulates uptake of inorganic phosphate used for the formation of energy-rich phosphate compounds necessary for muscle cell contractility [Marcinkowska, 2001; Bellido and Boland, 1991; Rodman and Baker, 1978]. In addition, low vitamin D levels may cause secondary hyperparathyroidism and excess PTH had been shown to enhance the degradation of muscle proteins [Baczynski et al. 1985]. An effect of vitamin D on muscle cell function is further supported by studies on muscle biopsies and electrophysiological examinations. Atrophy of type II muscle fibres as well as nonspecific histological abnormalities such as fatty infiltration, interstitial fibrosis and sarcolemmal nuclear proliferation have been shown in muscle biopsies from subjects with vitamin D deficiency and treatment with vitamin D has been shown to reverse these changes, including an increased number and cross-sectional area of type II fibres [Sato et al. 2005; Boland, 1986; Sorensen et al. 1979]. In electrophysiological studies, low vitamin D levels have been shown to cause an abnormal pattern with a reduced motor unit potential duration and amplitude and an increased percentage of polyphasicity without concomitant signs of denervation [Boland, 1986; Skaria et al. 1975].

In conclusion, several lines of evidence support an effect of vitamin D on muscle function and findings from RCTs have shown beneficial effects of vitamin D supplementation in the elderly. However, an effect is not universally present as more papers showing a lack of an effect have been published than papers showing beneficial effects. Explanations for the discrepant results are not obvious, as no general characteristics seem to separate studies showing beneficial effects from studies showing no effect of an improved vitamin D status. Further studies should try to replicate findings from the studies showing beneficial effects with predefined sample size calculations in order to assure a proper statistical power. Moreover, as low vitamin D levels are common in the general population, more studies are needed in younger subjects in order to assess potential harmful effects of vitamin D insufficiency on neuromuscular health in subjects below the age of 50 years.

Footnotes

This work was supported by a grant (# 09-070940) from The Danish Council for Independent Research in Medical Sciences (FSS).

The author reports no conflict of interest in preparing this manuscript.

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