A Randomized Controlled Trial of the Effects of Vitamin D on Muscle Strength and Mobility in Older Women with Vitamin D Insufficiency

Kun Zhu, PhD; Nicole Austin, PhD; Amanda Devine, PhD; David Bruce, MD; Richard L. Prince, MD

J Am Geriatr Soc. 2010;58(11):2063-2068. 

Abstract and Introduction

Abstract

Objectives: To evaluate the effects of vitamin D treatment on muscle strength and mobility in older women with vitamin D insufficiency.
Design: One-year population-based, double-blind, randomized, controlled trial.
Setting: Perth, Australia (latitude 32°S).
Participants: Three hundred two community-dwelling ambulant elderly women aged 70 to 90 with a serum 25-hydroxyvitamin D (25(OH)D) concentration less than 24 ng/mL.
Intervention: Vitamin D2 1,000 IU/d or identical placebo; calcium citrate (1 g calcium/d) in both groups.
Measurements: Lower limb muscle strength and mobility as assessed using the Timed Up and Go Test (TUAG).
Results: At baseline, mean±standard deviation serum 25(OH)D was 17.7±4.2 ng/mL; this increased to 24.0±5.6 ng/mL in the vitamin D group after 1 year but remained the same in the placebo group. For hip extensor and adductor strength and TUAG, but not for other muscle groups, a significant interaction between treatment group and baseline values was noted. In those with baseline values in the lowest tertile, vitamin D improved muscle strength and TUAG more than calcium alone (mean (standard error): hip extensors 22.6% (9.5%); hip adductors 13.5% (6.7%), TUAG 17.5% (7.6%), P<.05). Baseline 25(OH)D levels did not influence patient response to supplementation.
Conclusion: Vitamin D therapy was observed to increase muscle function in those who were the weakest and slowest at baseline. Vitamin D should be given to people with insufficiency or deficiency to improve muscle strength and mobility.

Introduction

Older people are at risk of inadequate vitamin D production in the skin because of less sun exposure and poorer ability of the skin to synthesize vitamin D.[1] Low vitamin D status has been implicated as a cause of falling in elderly institutionalized women[2,3] and in community-dwelling women.[4,5] Despite this, the mechanism of action of vitamin D on falls propensity remains unclear and is an important question that arises in conjunction with the question of clinical efficacy. It has been suggested that the effects of vitamin D on de novo protein synthesis mediates its effects on muscle[6,7] through receptors for 1,25(OH)2D in muscle tissue. Specifically, it has been suggested that it is the active vitamin D metabolite (1,25(OH)2D) that binds to a specific vitamin D nuclear receptor (VDR) in the muscle tissue.[8–10]

Several cross-sectional studies have shown that low vitamin D status is related to lower muscle strength and lower physical performance in older people,[11–14] but prospective randomized controlled trials on potential mechanisms have not provided a clear answer. Whereas some vitamin D supplementation studies showed an effect of vitamin D on improving lower extremity muscle strength and function in older people,[2,15,16] others have failed to show any effect.[17–19]

Moreover, there are few studies on the effects of vitamin D supplementation on muscle strength and mobility in older people with low vitamin D status, although a recent study has suggested benefit on mediolateral sway in participants who had large sway at baseline.[20] The aim of this study was to compare the effects of vitamin D2 treatment 1,000 IU/d with placebo for 1 year on muscle strength and mobility in older community-dwelling women with vitamin D insufficiency. The beneficial effects of the intervention on falls risk have been published previously.[5]

Materials and Methods

Subjects

Three hundred two women aged 70 to 90 were recruited between April 2003 and October 2004 in Perth, Australia (latitude 32°S). The recruitment procedure has been reported elsewhere;[5] in brief, participants were recruited from the following three sources: the emergency departments of teaching hospitals, the local community home nursing service (Silver Chain), and the Electoral Roll. The inclusion criteria were a plasma 25(OH)D concentration less than 24 ng/mL and a history of at least one fall in the previous 12 months. Exclusion criteria were current consumption of vitamin D or bone or mineral active agents apart form calcium, a bone mineral density (BMD) Z-score at the total hip site of less than −2.0, medical conditions or disorders that influence bone mineral metabolism; a fracture in the past 6 months, a Mini-Mental State Examination score less than 24 or the presence of significant neurological conditions likely to substantially impair balance or physical activity such as stroke, and Parkinson's disease.

This study was conducted according to the guidelines laid down in the Declaration of Helsinki, and the Human Research Ethics Committee of the Sir Charles Gairdner Hospital approved all procedures involving human subjects. Written informed consent was obtained from each participant. The study was registered with the Australian Clinical Trials Registry (registration number ACTRN012606000331538).

Treatment

Participants received 1,000 mg/d of calcium as calcium citrate (Citracal, Mission Pharmacal, Key Pharmaceutical Pty Ltd, Rhodes, Australia) for 1 year as two calcium tablets in the morning with breakfast and two calcium tablets with the evening meal. They were randomized to receive 1,000 IU ergocalciferol (vitamin D2) per day or identical placebo (Ostelin, Boots Healthcare, North Ryde, Australia) consumed with the evening meal for 1 year.

An independent research scientist who labelled the bottles and dispensed the study medications to subjects generated the randomization schedule to vitamin D or placebo, which was kept in the Pharmacy Department of the Sir Charles Gairdner Hospital. The randomization procedure used a random number generator with a block size of 10 to assign participants to vitamin D or placebo in a ratio of 1:1. The study subjects and study staff remained blinded to the treatment code until all data had been entered and evaluated for accuracy and the a priori hypotheses reviewed. Adherence to the study medications was established by counting tablets returned at the clinic visits at 6 and 12 months.

Muscle Strength and Mobility

At baseline and 12 months, ankle dorsiflexion, knee flexor, knee extensor, hip abductor, hip flexor, hip extensor, and hip adductor strength were assessed using a strain gauge. The subjects were requested to exert a maximal muscle contraction against the strain gauge after one practice. The best of three attempts was recorded for each muscle group. The coefficient of variation (CV) error was between 14% and 20% for the different muscle groups.

Mobility functioning was measured using the Timed Up and Go Test (TUAG), which timed subjects while getting up, walking 3 m, turning, returning to chair and sitting down again.[21] The CV error was 7%.

Biochemistry Analysis

At baseline and 12 months, venous blood was collected after an overnight fast, and serum 25(OH)D concentrations were assessed using radioimmunoassay (DiaSorin, Stillwater, MN).

Other Assessments

At screening, demographic information including smoking history, use of community services, medications, patient recall of prevalent morbidity, and socioeconomic status was obtained. Calcium intake was assessed using a food frequency questionnaire developed in a previous study.[22]] This questionnaire includes 39 food items and uses the Australian Tables of Food Composition—NUTTAB 90 database, a nutritional database that uses chemical analysis of Australian foods. Activity levels were calculated in kcal/d using a validated method using body weight, number of hours and type of physical activity, and energy costs of such activities.[23,24] Weight and height were measured at baseline and 12 months with light cloths and without shoes.

Sample Size Calculation and Statistical Analysis

Power calculations were performed before commencement of the study. As the primary purpose of this trial was to study the effects of vitamin D supplementation on risk of falling, the sample size was calculated in that 113 subjects were needed in each group to detect a relative risk reduction of 0.37 in a population with a 1-year fall risk of 0.6. Allowing for 30% dropout, the sample size was determined to be 150 per group. At this sample size, a 10% difference in muscle strength or TUAG could be detected at 80% power and 5% level of significance.

Descriptive statistics are reported as means±standard deviations and differences as means±standard errors of the mean for all variables, unless otherwise stated. The normality of continuous variables was checked through the construction of histograms. One variable that was not normally distributed (TUAG) was log-transformed. Baseline values between the two groups were compared using the Student t-test or Mann-Whitney test when appropriate. A linear regression model was used to test whether baseline values (baseline 25(OH)D or baseline muscle strength and mobility measurements) were effect modifiers for the effects of ergocalciferol supplementation on muscle strength and mobility, with changes from baseline to 12 months in outcome measures as the dependent variable and treatment group, baseline values, and the interaction terms of baseline value and treatment group as the independent variables. If there was a significant interaction, subgroup analyses were conducted according to tertile of baseline value. The normality and independence of the residuals and the homogeneity of variance of each model were checked using residual plots (normal probability plot and plot of residuals vs predicted values). All tests were two tailed, and significance was set at P<.05. The data analyses were performed with SPSSPC for Windows (SPSS, version 15, Chicago, IL).

Results

Recruitment, Retention, and Compliance

Three thousand six hundred ninety-eight subjects responded to letters asking them to join the study and were contacted by telephone; of these, 827 attended a clinic screening visit, and of these, 302 who met the inclusion criteria entered the study (Figure 1). Participant withdrawals were not significantly different between the two groups. Excluding the 14 subjects who did not have 12-month muscle strength and mobility measured, results on 129 and 132 patients in the vitamin D and control groups were used for this study (Figure 1). Medication discontinuations after recruitment were not significantly different between the two groups (Figure 1). There was no significant difference between the vitamin D group and the control group in adherence rate to study medication in subjects who remained on medication as determined from tablet counting (86.7% and 86.8%, respectively).

Figure 1.

 

Participant flow through the study.

Participant Characteristics

There were no significant differences between the vitamin D and control groups in any baseline characteristics listed in and . The majority (96.6%) of subjects were Caucasian, more than 80% rated their fitness as average for age or above, and 16.5% needed to use a walking aid. The mean baseline calcium intake was 1,087±456 mg/d.

Table 1.  Subject Characteristics at Baseline

Characteristic Vitamin D+Calcium (n=129) Placebo+Calcium (n=132)
Age, mean ± SD 76.8 ± 4.2 77.0 ± 4.8
Weight, kg, mean ± SD 73.7 ± 14.2 71.8 ± 12.8
Height, cm, mean ± SD 158.0 ± 6.4 159.5 ± 6.0
Body mass index, kg/m2, mean ± SD 29.5 ± 5.4 28.2 ± 4.9
Dietary calcium intake, mg/d, mean ± SD 1085 ± 500 1088 ± 411
Physical activity, kcal/d, median (interquartile range)* 61 (10, 194) 53 (17, 139)
Mini-Mental State Examination score, mean ± SD 28.6 ± 1.4 28.4 ± 1.6
Ethnicity, %
   Caucasian 96.1 97.0
   Asian 3.1 3.0
   Other 0.8 0
Fitness self-rating, %
   Unfit 9.6 6.3
   Below average fitness for age 9.6 8.6
   Average fitness for age 60.8 66.4
   Above fitness for age 15.2 17.2
   Very fit 4.8 1.6
Using walking aid, % 17.1 15.9

* There were no significant differences between the two groups in baseline characteristics in the table (Student t-test or Mann-Whitney test).
SD=standard deviation.

Table 2.  Vitamin D Status, Mobility, and Muscle Strength at Baseline and 1 Year

Factor Mean ± Standard Deviation
Vitamin D+Calcium (n=129) Placebo+Calcium (n=132)
Baseline 1 year Baseline 1 year
Serum 25-hydroxyvitamin D, ng/mL 18.1 ± 5.0 24.0 ± 5.6* 17.7 ± 5.2 18.0 ± 5.4
Timed Up and Go Test, seconds 11.0 ± 5.3 8.1 ± 3.9* 10.8 ± 4.6 9.0 ± 7.0*
Lower limb muscle strength, kg
   Ankle dorsiflexion 11.6 ± 4.4 10.9 ± 3.7* 11.8 ± 4.2 10.9 ± 4.0*
   Knee flexor 11.8 ± 3.6 12.9 ± 3.5* 11.9 ± 3.7 13.0 ± 3.9*
   Knee extensor 18.3 ± 6.4 18.0 ± 5.0 18.8 ± 7.3 18.3 ± 5.5
   Hip extensor 14.6 ± 5.7 17.2 ± 5.2* 14.4 ± 5.3 16.9 ± 6.2*
   Hip abductor 12.3 ± 4.2 14.5 ± 4.1* 12.2 ± 5.0 14.1 ± 4.9*
   Hip flexor 14.5 ± 5.0 15.4 ± 4.2* 14.5 ± 5.7 15.4 ± 4.8*
   Hip adductor 14.4 ± 4.7 16.4 ± 4.4* 14.7 ± 5.0 16.3 ± 5.2*

* Significantly different from baseline, P<.05.

Effects on Vitamin D Status

Mean baseline 25(OH)D concentration was 17.7±4.2 ng/mL, with no significant difference between the two groups. Sixty-six percent of subjects had baseline 25(OH)D concentrations below 20 ng/mL. At 12 months, the vitamin D group had significantly higher serum 25(OH)D concentrations than the control group (). In the vitamin D group, at 12 months, 79% of subjects had 25(OH)D levels greater than 20 ng/mL, and 47% had 25(OH)D level greater than 24 ng/mL.

Table 2.  Vitamin D Status, Mobility, and Muscle Strength at Baseline and 1 Year

Factor Mean ± Standard Deviation
Vitamin D+Calcium (n=129) Placebo+Calcium (n=132)
Baseline 1 year Baseline 1 year
Serum 25-hydroxyvitamin D, ng/mL 18.1 ± 5.0 24.0 ± 5.6* 17.7 ± 5.2 18.0 ± 5.4
Timed Up and Go Test, seconds 11.0 ± 5.3 8.1 ± 3.9* 10.8 ± 4.6 9.0 ± 7.0*
Lower limb muscle strength, kg
   Ankle dorsiflexion 11.6 ± 4.4 10.9 ± 3.7* 11.8 ± 4.2 10.9 ± 4.0*
   Knee flexor 11.8 ± 3.6 12.9 ± 3.5* 11.9 ± 3.7 13.0 ± 3.9*
   Knee extensor 18.3 ± 6.4 18.0 ± 5.0 18.8 ± 7.3 18.3 ± 5.5
   Hip extensor 14.6 ± 5.7 17.2 ± 5.2* 14.4 ± 5.3 16.9 ± 6.2*
   Hip abductor 12.3 ± 4.2 14.5 ± 4.1* 12.2 ± 5.0 14.1 ± 4.9*
   Hip flexor 14.5 ± 5.0 15.4 ± 4.2* 14.5 ± 5.7 15.4 ± 4.8*
   Hip adductor 14.4 ± 4.7 16.4 ± 4.4* 14.7 ± 5.0 16.3 ± 5.2*

* Significantly different from baseline, P<.05.

Effects on Muscle Strength and Mobility Function

Over the 12-month study, there was significant improvement in knee flexor strength and all hip muscle strength and mobility as measured using the TUAG in both groups. Ankle dorsiflexion strength reduced significantly in both groups, and there was no change in knee extensor strength after 12 months ().

Table 2.  Vitamin D Status, Mobility, and Muscle Strength at Baseline and 1 Year

Factor Mean ± Standard Deviation
Vitamin D+Calcium (n=129) Placebo+Calcium (n=132)
Baseline 1 year Baseline 1 year
Serum 25-hydroxyvitamin D, ng/mL 18.1 ± 5.0 24.0 ± 5.6* 17.7 ± 5.2 18.0 ± 5.4
Timed Up and Go Test, seconds 11.0 ± 5.3 8.1 ± 3.9* 10.8 ± 4.6 9.0 ± 7.0*
Lower limb muscle strength, kg
   Ankle dorsiflexion 11.6 ± 4.4 10.9 ± 3.7* 11.8 ± 4.2 10.9 ± 4.0*
   Knee flexor 11.8 ± 3.6 12.9 ± 3.5* 11.9 ± 3.7 13.0 ± 3.9*
   Knee extensor 18.3 ± 6.4 18.0 ± 5.0 18.8 ± 7.3 18.3 ± 5.5
   Hip extensor 14.6 ± 5.7 17.2 ± 5.2* 14.4 ± 5.3 16.9 ± 6.2*
   Hip abductor 12.3 ± 4.2 14.5 ± 4.1* 12.2 ± 5.0 14.1 ± 4.9*
   Hip flexor 14.5 ± 5.0 15.4 ± 4.2* 14.5 ± 5.7 15.4 ± 4.8*
   Hip adductor 14.4 ± 4.7 16.4 ± 4.4* 14.7 ± 5.0 16.3 ± 5.2*

* Significantly different from baseline, P<.05.

Because there was no between-group treatment effect on the averages of these variables, interactions between treatment group and baseline muscle strength and mobility were investigated using a regression approach to test the hypothesis that vitamin D was most effective in the weakest and slowest individuals. For hip extensor and adductor strength, but not for the other muscle groups, a significant interaction between treatment group and baseline muscle strength was noted. To explore this effect further, subjects were grouped according to tertile of baseline muscle strength. In those with baseline values in the lowest tertile, hip extensor strength (22.6% (9.5%), P=.0s) and adductor strength (13.5% (6.7%), P=.048) improved significantly in the vitamin D group at 12 months (). Similarly, TUAG showed a significant interaction between treatment group and baseline value, such that the lowest tertile of the vitamin D group was significantly faster at 12 months (17.5% (7.6%), P=.02) than the control group (Figure 2). These effects remained after adjustment for baseline age and baseline 25(OH)D concentrations.

Table 3.  Change in Hip Extensor and Adductor Strength According to Baseline Tertile Values

Tertile of Strength (kg) Mean (Standard Error)
Absolute Change (kg) % Difference in Change (Vitamin D–Placebo)
Vitamin D Placebo
Hip extensor
   Lowest (≤11) 5.2 (0.7) 3.1 (0.8) 22.6 (9.5)*
   Middle (12–15) 3.5 (0.6) 4.3 (0.7) −3.8 (5.9)
   Highest (≥16) 0.1 (0.7) 0.7 (0.8) −1.1 (5.1)
Hip adductor
   Lowest (≤12) 3.4 (0.5) 2.1 (0.6) 13.5 (6.7)*
   Middle (13–16) 2.2 (0.5) 3.2 (0.5) −6.8 (4.5)
   Highest (≥17) −0.4 (0.6) −0.3 (0.6) −0.2 (4.2)

* The increase in strength was significantly greater in the vitamin D group than in the placebo group in the same tertile, P<.05.

Figure 2.

 

Change in Timed Up and Go Test over 12 months according to baseline tertile. Error bars represent standard errors.

The effect of baseline 25(OH)D was examined to investigate whether those with low baseline vitamin D had better muscle strength and mobility response to supplementation than those with higher baseline 25(OH)D levels. Baseline 25(OH)D level was not an effect modifier for the effects of ergocalciferol supplementation on muscle strength and mobility (data not shown).

Discussion

The present study found that, in older women with low vitamin D status receiving calcium, ergocalciferol supplementation improved muscle strength in subjects with baseline muscle strength and mobility in the lowest tertile. Mobility as reflected by the TUAG improved significantly in those in the slowest tertile at baseline with supplementation.

Previous intervention studies on the effects of vitamin D on lower extremity muscle strength and function have yielded inconsistent results. Whereas some trials showed an effect of vitamin D on improving lower extremity muscle strength and function in older people,[2,15,16] others did not.[17–19] Most of these studies included male and female participants who were not selected for low vitamin D status. In one recent study of 226 men and women aged 70 and older with vitamin D insufficiency (serum 25(OH)D 6–20 ng/mL), 8,400 IU vitamin D weekly supplementation for 16 weeks increased serum 25(OH)D from 14 to 26 ng/mL. The intervention reduced mediolateral sway in participants who had large sway but not those who had normal sway at baseline.[20] Consistent with this, the present study showed that, in older women with baseline serum 25(OH)D levels less than 24 ng/mL, vitamin D supplementation significantly improved muscle strength in participants with low baseline muscle strength.

The TUAG includes basic mobility skills and is an effective method of assessing functional mobility in older adults.[21] It has also been shown to be a sensitive and specific measure for identifying community-dwelling older adults aged 65 and older who are prone to fall.[25] The results of the current study showed that supplementation of vitamin D2 1,000 IU/d improved TUAG time 17.5% in participants with baseline values longer than 12 seconds. This is of clinical significance, because 12 seconds has been suggested to be the cutoff point for normal mobility.[26] A previous study showed that vitamin D supplementation could improve neuromuscular coordination in older people with serum 25(OH)D concentrations less than 30 nmol/L (12 ng/mL) and a history of falling.[27] Therefore, the improvement on the TUAG could be related to improved muscle strength and neuromuscular function.

The current study used vitamin D2 as the supplement, and although some studies have reported that vitamin D2 is not as effective as vitamin D3 in maintaining serum 25(OH)D concentrations,[28,29] a recent study showed that vitamin D2 was as effective as vitamin D3 in maintaining serum 25(OH)D concentrations.[30] Epidemiological studies have suggested that, for optimal lower extremity strength, serum 25(OH)D concentrations greater than 20 ng/mL are desirable.[31,32] In the present study, 1,000 IU of ergocalciferol resulted in 80% of subjects in the vitamin D group achieving a serum 25(OH)D concentration greater than 20 ng/mL. Despite this, it could be argued that the dose of vitamin D used was suboptimal, and whether higher doses of vitamin D may provide further functional benefit is being actively pursued.

For muscle strength measurements based on voluntary contractions, subjects may learn how to perform a "good" test. In the present study, participants were given three attempts for each muscle group to reduce potential learning effect bias. In addition, the double-blind randomized placebo-controlled design of the present study ensured that any "learning effect" would occur in both groups and would not introduce bias to the study. A post hoc hypothesis that treatment was most effective in the weakest and slowest replaced the primary hypothesis that vitamin D reduced falling by improving mean muscle strength and mobility in all subjects. Multiple testing was not adjusted for in the subgroup analysis, so the results should be accepted with some caution. Nevertheless, similar effects were observed in two muscle groups and the TUAG in the present study and in a previous study.[20] Finally, the subjects were Caucasian community-dwelling elderly women with low vitamin D status, so the interpretations of these findings are limited to this population.

Conclusion

In conclusion, vitamin D supplementation in older individuals receiving calcium improved hip muscle strength and mobility in participants with low baseline values. Given the importance of maintaining physical performance in older people to maintain a healthy and independent life in the community, vitamin D should be added to those with insufficiency or deficiency to improve muscle function.

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