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Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis - pdf attached
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Osteoporosis International
Volume 22, Number 3, 859-871, DOI: 10.1007/s00198-010-1407-y
K. A. Stockton, K. Mengersen, J. D. Paratz, D. Kandiah and K. L. Bennell
(1) School of Medicine, University of Queensland, Brisbane, QLD, Australia
(2) Department of Mathematics, Queensland University of Technology, Brisbane, QLD, Australia
(3) Centre for Health, Exercise and Sports Medicine, University of Melbourne, Melbourne, VIC, Australia
(4) Department Rheumatology, Royal Brisbane and Women's Hospital, Level 7, Ned Hanlon Building, Butterfield St, Herston, QLD, 4029, Australia
"The aim of this systematic review was to evaluate the effect of vitamin D supplementation on muscle strength in adults. The majority of studies were of medium to high methodological quality as assessed on the PEDro scale. This systematic review demonstrates no significant effect of vitamin D supplementation on grip strength, knee extension strength, and knee flexion strength in participants with 25(OH)D levels >25 nmol/L. However, a limited number of studies demonstrate a positive effect of vitamin D supplementation on proximal muscle [35, 36], calf [38], and grip strength [38] in participants with 25(OH)D levels ≤25 nmol/L."
"Vitamin D receptors have been identified in muscle cells [5, 6] which supports the concept of a direct effect of vitamin D on muscle tissue. However, very few studies have explored this. Vitamin D deficiency is reported to cause proximal muscle weakness with a reduction in type 2 muscle fibres [44]. Type 2 fibres are fast twitch and are recruited in activities of high intensity but short duration. An uncontrolled study [45] on elderly women demonstrated an increase in cross-sectional area and number of type 2A muscle fibres in vastus lateralis following 3-6 months supplementation
with 1α hydroxyvitamin D"
"Conclusion: Based on studies included in this systematic review; while vitamin D supplementation may not be effective at improving muscle strength in vitamin D replete adults, there is evidence that supplementation may increase muscle strength in adults with 25(OH)D ≤25 nmol/L. It would be difficult to ethically justify randomised placebo-controlled trials of vitamin D supplementation in patients with clearly established deficiency (<25 nmol/L) due to the implications on calcium and phosphate homeostasis and thus bone health. Further, well-designed randomised controlled trials using appropriate outcome measures need to be conducted investigating the effect of vitamin D supplementation on muscle fibre composition and its relationship to proximal muscle power and physical function in patients with insufficient levels of vitamin D (25-50/75 nmol/L). In addition, there is a distinct lack of randomised controlled trials investigating vitamin D supplementation in disease-specific populations where Vitamin D deficiency is common."
Abstract
Summary
This systematic review demonstrates that vitamin D supplementation does not have a significant effect on muscle strength in vitamin D replete adults. However, a limited number of studies demonstrate an increase in proximal muscle strength in adults with vitamin D deficiency.
Introduction
The purpose of this study is to systematically review the evidence on the effect of vitamin D supplementation on muscle strength in adults.
Methods
A comprehensive systematic database search was performed. Inclusion criteria included randomised controlled trials (RCTs) involving adult human participants. All forms and doses of vitamin D supplementation with or without calcium supplementation were included compared with placebo or standard care. Outcome measures included evaluation of strength. Outcomes were compared by calculating standardised mean difference (SMD) and 95% confidence intervals.
Results
Of 52 identified studies, 17 RCTs involving 5,072 participants met the inclusion criteria. Meta-analysis showed no significant effect of vitamin D supplementation on grip strength (SMD -0.02, 95%CI -0.15,0.11) or proximal lower limb strength (SMD 0.1, 95%CI -0.01,0.22) in adults with 25(OH)D levels >25 nmol/L. Pooled data from two studies in vitamin D deficient participants (25(OH)D <25 nmol/L) demonstrated a large effect of vitamin D supplementation on hip muscle strength (SMD 3.52, 95%CI 2.18, 4.85).
Conclusion
Based on studies included in this systematic review, vitamin D supplementation does not have a significant effect on muscle strength in adults with baseline 25(OH)D >25 nmol/L. However, a limited number of studies demonstrate an increase in proximal muscle strength in adults with vitamin D deficiency.
Introduction
It is estimated that more than a billion people worldwide are deficient in vitamin D [1]. Those most at risk include older people in residential care [2], darker-skinned women [3] (particularly if veiled) and people with medical conditions that require sun avoidance or cause malabsorption [4]. The prime source of vitamin D is the conversion of 7-dehydrocholesterol to previtamin D3 in the skin by solar ultraviolet B radiation. Very little vitamin D is obtained from the diet.
It is well established that vitamin D is an integral part of calcium and phosphate homeostasis and thus essential to bone health. In addition, vitamin D receptors have been identified on many other tissues including skeletal muscle [5, 6]. Severe vitamin D deficiency causes rickets in children and osteomalacia in adults resulting in proximal muscle weakness. Muscle atrophy, particularly of type 2 fibres in vitamin D deficiency has been described histopathologically [7, 8]. There is conflicting evidence as to whether Vitamin D deficiency contributes to proximal muscle weakness. Some studies demonstrating an association [9-12], others finding no relationship between vitamin D levels and weakness [13-15]. A recent study investigating the relationship between quadriceps strength and vitamin D levels [16] found a significant association with univariate analysis. However, there were no statistically significant relationship once potential confounders such as physical activity, age, and comorbidities were controlled for. Thus, the effect of vitamin D supplementation on muscle strength has not been clearly established.
A systematic review conducted in 2003 [17] concluded that Vitamin D alone cannot be recommended for use in clinical practice where the primary aim is to improve muscle strength or physical function or reduce the risk of falling in frail elderly people. This review [17] investigated the effect of vitamin D supplementation on muscle strength, physical function, and falls in the elderly. However, there was no rating regarding the methodological quality of the included studies. In addition, effect sizes and confidence intervals were only calculated for the outcome "falls". Further randomised controlled trials (RCTs) have been published since 2003. In addition, the last few years has seen an increase in articles reporting the benefits of vitamin D on muscle strength in both peer-reviewed journals [18] and public health literature. The aim of this current systematic review was to critically review the evidence on the effect of vitamin D supplementation on outcome measures specifically relating to muscle strength including all adults, not just the elderly. Thus, the research question is: Does vitamin D supplementation result in improved strength in adults?
Discussion
The aim of this systematic review was to evaluate the effect of vitamin D supplementation on muscle strength in adults. The majority of studies were of medium to high methodological quality as assessed on the PEDro scale. This systematic review demonstrates no significant effect of vitamin D supplementation on grip strength, knee extension strength, and knee flexion strength in participants with 25(OH)D levels >25 nmol/L. However, a limited number of studies demonstrate a positive effect of vitamin D supplementation on proximal muscle [35, 36], calf [38], and grip strength [38] in participants with 25(OH)D levels ≤25 nmol/L. Studies investigating vitamin D supplementation in falls and fracture reduction have recommended that a minimum of 800 IU daily is required. This recommendation is in the absence of baseline (and often post-treatment) 25(OH)D levels. The majority of studies included in this current systematic review provided baseline and post-treatment 25(OH)D serum levels. With all but one study achieving 25(OH)D levels of >50 nmol/L regardless of type or dose of supplementation. Baseline 25(OH)D levels in the study that did not achieve >50 nmol/L of vitamin D in the supplemented group [27] were bordering on deficiency (median 26 nmol/L). The treatment group received 600,000 IU D2 once by injection with outcome measures taken at 6 months. It has been suggested that D2 is more rapidly metabolised than D3, thus a large once off dose may be inadequate at 6 months given the baseline 25(OH)D status [40, 41]. The role of calcium in combination with vitamin D on muscle function is not clear and warrants further investigation given the recent meta-analyses demonstrating that to reduce fractures, vitamin D must be given in conjunction with calcium [42, 43].
Calcitriol (1,25(OH)2D vitamin D) was the supplement of choice in one of the included studies [28]. However, due to its expense and the risk of hypercalcaemia, it is only recommended as a supplement in those patients who cannot convert standard vitamin D supplement to activated vitamin D, such as severe renal disease.
Vitamin D receptors have been identified in muscle cells [5, 6] which supports the concept of a direct effect of vitamin D on muscle tissue. However, very few studies have explored this. Vitamin D deficiency is reported to cause proximal muscle weakness with a reduction in type 2 muscle fibres [44]. Type 2 fibres are fast twitch and are recruited in activities of high intensity but short duration. An uncontrolled study [45] on elderly women demonstrated an increase in cross-sectional area and number of type 2A muscle fibres in vastus lateralis following 3-6 months supplementation with 1α hydroxyvitamin D. Only one study in this current review [35] incorporated muscle fibre analysis and this was in patients with deficient 25(OH)D whereby a significant increase in strength and type 2 fibre cross-sectional area and percentage of vastus lateralis muscle was found. Type 2 muscle fibres are the first to be recruited in balance and preventing a fall which may explain the inverse association between 25(OH)D levels and falls [46, 47]. In addition, a recent study on healthy young women [48] demonstrated an inverse relationship between skeletal muscle fat and 25(OH)D levels. The effect of this relationship on muscle strength and/or function has not been established. Future studies investigating the effect of vitamin D supplementation on muscle should incorporate analysis of muscle composition.
Isokinetic dynamometry provides an objective, reproducible evaluation of strength more closely aligned to activities of daily living than isometric evaluation. However, only two studies in this review [28, 38] utilised isokinetic dynamometry. Methods used for evaluation of strength in the other studies carry an increased risk of error. Accurate measures from HHD and strain gauge rely on ensuring that the force transducer is placed in exactly the same position on the limb at each measurement time point and that there is adequate stabilisation of the body part being tested [49] both of which were not mentioned in most studies [23, 27, 32, 34]. In addition, with HHD, the tester must be able to exert a force greater than the muscle being tested [50]. Measurement error of 1RM is high and relies on adequate familiarisation of the participant and experience of the investigator [51]. MMT as measured by two studies [35, 36] has been found to be inaccurate at higher grades. However, the baseline strength of the participants in both studies was very low, thus MMT would be less prone to error and possibly a suitable measure for this population.
All studies included in this systematic review investigated maximal muscle strength which is only one component of muscle function. In activities of daily living, maximal force is rarely required. Rate of force development (RFD) may be more appropriate to test given the evidence regarding preferential atrophy of type 2 muscle fibres with vitamin D insufficiency. RFD can be measured using isokinetic/isometric contraction with electromyography or functionally such as use of jumping mechanography. Jumping mechanography has been used in a cross-sectional study of 99 post-menarchal 12-14-year-old girls demonstrating a relationship between 25(OH)D level, jump velocity, and power. Due to the cross-sectional design, causality cannot be determined; however, the outcome measure utilised may be preferable to measuring maximal strength alone when investigating the effect of vitamin D supplementation on muscle function.
Limitations
A positive effect of vitamin D supplementation on muscle if higher than 25(OH)D levels are achieved cannot be excluded. Recently, the International Osteoporosis Foundation Position Statement on Vitamin D has been published [52]. The majority of the working party members felt that based on RCTs in falls and fracture reduction, the optimal level for serum 25(OH)D is 75 nmol/L. The optimal level of 25(OH)D for muscle is not known. This review found no evidence that vitamin D supplementation improved muscle strength in patients with levels >25 nmol/L. Measuring proximal hip muscle strength may yield a different outcome given that Moreira-Pfrimer et al. [33] found positive effect of vitamin D supplementation on hip flexion strength in participants with baseline 25(OH)D 25-50 nmol/L. It is difficult to draw conclusions regarding this as Moreira-Pfrimer et al. was the only study included in this review that measured hip muscle strength in participants with baseline 25(OH)D >25 nmol/L and effect sizes could not be calculated due to insufficient data.
Population studied
Despite inclusion criteria aiming to include adults >18 years of age only one study included participants <60 years of age [38].
A further limitation of this review is the possible effect of publication bias. An attempt was made to decrease the likelihood of this occurring by searching for registered trials in the area and contacting key researchers in the field where appropriate. Only English-language studies were included; however, as only two non-English language RCTs were identified, this is unlikely to have biassed the outcomes.
Conclusion
Based on studies included in this systematic review; while vitamin D supplementation may not be effective at improving muscle strength in vitamin D replete adults, there is evidence that supplementation may increase muscle strength in adults with 25(OH)D ≤25 nmol/L. It would be difficult to ethically justify randomised placebo-controlled trials of vitamin D supplementation in patients with clearly established deficiency (<25 nmol/L) due to the implications on calcium and phosphate homeostasis and thus bone health. Further, well-designed randomised controlled trials using appropriate outcome measures need to be conducted investigating the effect of vitamin D supplementation on muscle fibre composition and its relationship to proximal muscle power and physical function in patients with insufficient levels of vitamin D (25-50/75 nmol/L). In addition, there is a distinct lack of randomised controlled trials investigating vitamin D supplementation in disease-specific populations where Vitamin D deficiency is common.
RESULTS - see pdf attached
Baseline 25(OH)D level ≤25 nmol/L
Four studies with a total of 465 participants with baseline 25(OH)D <25 nmol/L were identified [26, 35, 36, 38]. Three of the studies included participants from geriatric inpatient settings [26, 35, 36], the remaining study was on healthy young adults [38]. One study on inpatient geriatric participants derived a strength score from functional activities and found no significant difference between groups. A recent study on healthy, young adults demonstrated a statistically significant difference between treatment and control groups in grip strength (p < 0.001) and calf strength (p = 0.04), but not in pinch grip strength (p = 0.07).
Finally, two studies on a total of 360 institutionalised adults [35, 36] demonstrated a significant effect of vitamin D supplementation on proximal lower limb muscle strength (SMD 3.52, 95%CI 2.18, 4.85).
Study quality assessment
Table 2 provides a summary of the assessment of each study with respect to the criteria in the PEDro scale. A median score of 8 out of 10 (range 4-10; mode 8) on the PEDro scale [19] was found. Fifteen of the 17 studies reported random allocation [23-27, 29-36, 38, 39], with six studies also reporting concealment of treatment allocation [23, 27, 32, 35, 38, 39]. Twelve of the included studies reported blinding of the assessors to group allocation [23-27, 30, 32-36, 39] and 13 reported blinding of participants [23, 24, 26, 27, 29, 30, 32-35, 37-39]. Intention-to-treat analysis occurred in 13 studies [23-25, 27, 30-36, 38, 39]. Missing data meant that effect sizes could not be calculated for two papers [29, 33].
Intervention
The trials used a variety of vitamin D supplementation regimes. Six trials compared vitamin D alone with placebo [26, 27, 29, 32, 35, 37], four of which used ergocalciferol (D2) [26, 27, 29, 35], and two cholecalciferol (D3) [32, 37]. One study compared vitamin D metabolite (calcitriol) with placebo [28]. Treatment with a combination of vitamin D3 and calcium supplements was used in nine studies [23-25, 30, 31, 33, 34, 38, 39]. Five studies compared vitamin D and calcium with calcium alone [23, 25, 30, 33, 34], three studies investigated calcium and vitamin D versus placebo [24, 38, 39] and one study calcium and vitamin D versus nothing [31]. Finally, one study investigated vitamin D via sunlight exposure (with clearly defined exposed region and documented daily exposure time) to usual care [36]. Timeframes of the intervention period ranged from 12 weeks to 5 years with the mode being 6 months in duration. Two studies did not state baseline 25(OH)D level [24, 29], participants in four studies had baseline 25(OH)D >50 nmol/L [28, 30, 31, 34], the mean baseline 25(OH)D level was 25-50 nmol/L in seven studies [23, 25, 27, 32, 33, 37, 39], and <25 nmol/L in four studies [26, 35, 36, 38]. Baseline 1,25(OH)2D was within normal range in the study that used calcitriol as a supplement [28].
Outcome measures
Grip strength was an outcome in eight studies [23-25, 28, 30, 37-39] and was measured via hand held dynamometry (HHD) in seven studies [24, 25, 28, 30, 37-39] and using a vigorimeter in one study [23]. Pinch strength was measured in one study by a pinch gauge [38]. Knee extension strength was measured in eight studies [23, 25, 27, 28, 32-34, 39] by a variety of techniques. HHD was utilised in two studies [32, 33], four studies used a strain gauge [23, 27, 34, 39], one study employed a one repetition maximum (1RM) using a quadriceps table [25] and one used an isokinetic dynamometer [28]. Two studies measured leg press by 1RM [30, 31]. Two studies examined knee flexion, one via strain gauge [23] and one with an isokinetic dynamometer [28]. One study measured calf strength using isokinetic dynamometry [38]. Four studies measured a combination of proximal muscles: Moreira-Pfrimer et al. [33] measured hip flexion via HHD, Kukulijan et al. [31] measured bench press and latissimus dorsi pull down via 1RM, Sato et al. [36] computed a combined score of hip external and internal rotators and knee flexion and extension via manual muscle test (MMT). In the second study by this group a combined score of hip extension and flexion strength measured via MMT was utilised [35]. Finally, two studies derived a strength score from functional activities [26, 29]. It is questionable whether a derived score truly reflects strength; however, the studies have been included in this review for completeness.
Effect of vitamin D supplementation on muscle strength
End of trial 25(OH)D level-response to intervention
All but one study [27] achieved mean 25(OH)D levels >50 nmol/L in the vitamin D-treated group post-intervention (Table 4).
End of trial 1,25(OH)2D
Calcitriol was the supplement used in one study [28] with the treatment group achieving an increase in 1,25(OH)2D from 85.6 (33.7) to 95.4 pmol/L (baseline and post-supplementation within accepted normal range). However, seven of 50 patients in the treatment group required a reduction in dosage due to elevated serum or urinary calcium levels.
Muscle strength
The Q test for heterogeneity was nonsignificant (p < 0.05) with I 2 index ≤15% for all pooled studies when grouped according to baseline 25(OH)D level i.e.
≤25 and >25 nmol/L.
Baseline 25(OH)D level ≥25 nmol/L
Twelve studies with a total of 4,498 participants [23-25, 27, 28, 30-34, 37, 39].
Grip strength
Seven studies [23-25, 28, 30, 37, 39] on 3,648 participants with 25(OH)D >25 nmol/L measured grip strength. Vitamin D supplementation had no significant effect on grip strength (SMD -0.02, 95% CI -0.15, 0.11; Fig. 2).
Proximal trunk and upper limb strength
One study [31] on 180 community dwelling men with baseline 25(OH)D >25 nmol/L measured proximal upper limb muscles. There was no significant effect of vitamin D supplementation on bench press (SMD -0.23, 95% CI -0.66, 0.19) or lateral pull downs (SMD -0.32, 95% CI -0.75, 0.10).
Knee strength
Of the eight studies that measured knee extension strength in participants with 25(OH)D >25 nmol/L, one study [33] did not provide enough data to calculate effect sizes. This study on 46 institutionalised elderly participants with insufficient 25(OH)D levels found that supplementation with vitamin D improved knee extension strength by 24.7% whilst there was no statistically significant difference between baseline and end of study strength in the control group. Vitamin D supplementation had no significant effect on knee extension strength when data from the remaining seven studies (n = 1,010) was pooled (SMD 0.10, 95%CI -0.02, 0.29) [23, 25, 27, 28, 32, 34, 39]. Vitamin D supplementation had no significant effect on knee flexion strength when data was pooled from two studies [23, 28], total n = 220, (SMD 0.10, 95%CI -0.21, 0.41).
Leg press
There was no statistically significant difference between placebo and vitamin D groups in the two studies on 245 community dwelling vitamin D-sufficient men that measured leg press [30, 31] SMD 0.06 (95% CI -0.26, 0.39).
Hip strength
One study [33] measured hip strength but did not provide enough data to calculate effect sizes. This study [33] on 46 institutionalised elderly patients with 25(OH)D >25 nmol/L found that vitamin D supplementation improved hip flexion strength compared to control group in those participants with baseline 25(OH)D levels <50 nmol/L (p = 0.003). There was no statistically significant improvement in hip flexion strength in those patients with baseline 25(OH)D levels >50 nmol/L (p = 0.21).
Overall proximal lower limb strength
The results from knee extension, knee flexion, leg press, and hip strength in studies with 25(OH)D >25 nmol/L were combined to give an overall SMD of proximal lower limb strength from eight studies with a total of 1,255 adults. There was no significant effect of vitamin D supplementation on proximal lower limb strength (SMD 0.1, 95%CI -0.01, 0.22) in this pooled group of studies (Fig. 3).
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