Vitamin D Deficiency and Muscle Strength: Are They Related?

There have been several studies over the years that showed an association between reduced muscle strength or physical performance and low vitamin D status, that is low serum 25-hydroxyvitamin D (25OHD) levels. Generally, these studies show that subjects in the lower quartile of serum 25OHD levels performed less well on physical testing compared with those in the upper quartile. Most studies involved elderly subjects, and it is not clear whether physical performance declines because of age or due to a deficiency of vitamin D.

One long-term observational study in Holland followed an age-stratified sample of 1234 men and women who, on average, were 65 yr old at the beginning of the study and were followed for 6 yr (1). Lower levels of serum 25OHD were associated with lower physical performance. The tests performed were: time to walk 3 m and back, timed rise (five) from a chair, and a balance test (tandem stand-toe to heel for 10 sec); these are tests that measure proximal muscle strength, balance, and coordination. Subjects with serum 25OHD levels below 10 ng/ml performed less well compared with groups with higher serum 25OHD levels of 10–20 ng/ml and more than 30 ng/ml. The rate of decline was twice as fast in the group with the lowest serum 25OHD level compared with the highest levels, although when tests were adjusted for age, chronic disease, urbanization, body mass index, and alcohol intake, the changes were less pronounced.

Another observational study lasting 12 months in North America was a follow-up of 76-yr-old men and women (2). These investigators used the standard Short Physical Performance Battery (SPPB) (3), which involves three simple tests: 1) balance— the ability to stand with the feet together side by side, semitandem, and tandem positions; 2) the time to walk 8 feet; and 3) the time to rise from a chair five times. Each test has a maximum score of 4 and a total maximum score of 12. This test is often used in studies of physical performance in aging. In this study, the baseline serum 25OHD was not associated with a change in the SPPB, although half the subjects had serum 25OHD levels below 20 ng/ml. But those with lower SPPB scores did improve their scores and walking speed performance if their serum 25OHD increased over time from a serum 25OHD below 20 ng/ml to above 20 ng/ml; however, the numbers were small.

It is exactly these examples of association studies that have led to the idea that low levels of serum 25OHD are the cause of a decline in physical performance in the elderly. However, there are other studies that show declining physical performance with age in people with normal vitamin D status. But is it possible that low vitamin D status can be a contributor in part to poor physical performance in some elderly. In particular, the questions that interest us are as follows: Does vitamin D improve physical performance? If so, is it related to reaching a certain level of serum 25OHD? and Can we identify susceptible subjects from serum 25OHD levels? Only clinical trials can answer these questions.

There have been many intervention studies in the area of vitamin D and physical performance. However, less than one third of these studies meet the criteria for a randomized clinical trial. In this review, only studies that met the criteria for a randomized trial of vitamin D in elderly subjects were analyzed. There have been 14 studies, nine that used vitamin D3 and five that used D2. In 10 studies, calcium was given with vitamin D. The doses of vitamin D used were variable: 400 IU in four studies (4–7), 800 IU in four studies (4, 8–10), 1000 IU in two studies (11, 12), 2000 IU in one study (13), and 9000 IU in one study (14). There were three studies that used large doses: 600,000 IU by injection once (15); 300,000 IU oral once (16); and 150,000 IU monthly twice and then 90,000 IU monthly (17). In seven studies, there was a true placebo-control group, and in the other seven studies, the control group was given calcium supplements that varied in amounts from 500 to 1200 mg/d. There was one study of vitamin D in young adults in India (18) and one blinded study of calcitriol in an elderly group (19).

The length of study varied from 3 months to 5 yr, but most studies lasted between 6 and 12 months. An additional issue is the physical performance test. None performed the SPPB. The most consistently used tests were isometric measurement of knee extension strength and handgrip.

Some studies had measurements of serum 25OHD before and at the end of study. In a meta-analysis of almost the same studies discussed above, Stockton et al. (20) summarized the serum 25OHD values before and after study and found an increase in serum 25OHD from 50 to 70 nmol/liter (20–30 ng/ml). Their meta-analysis found no significant change in either handgrip strength or knee extension strength. However, one of the studies from Germany found a small increase in knee extension strength on 800 IU (P < 0.05) and an improvement in the timed up-and-go test (10). There were three studies that had much lower levels of serum 25OHD below 25 nmol/liter. In a study from Japan of post-stroke patients treated with 1000 IU vitamin D2 for 2 yr, serum 25OHD started at 13 nmol/liter and increased to 83 nmol/liter (5 to 33 ng/ml) (12). There was a significant improvement of 56% in hip flexor strength compared with a decrease of −24% on placebo and a 200% increase in both the number of type 2 muscle fibers and in their diameter compared with a decrease in the placebo group. In a study of elderly subjects from the United Kingdom treated for several months with 9000 IU vitamin D2 daily, serum 25OHD increased from 16 to 175 nmol/liter (7 to 70 ng/ml), but there was no improvement in activities of daily living (14). The third study from India was of young people, men and women, aged 31 yr with low levels of serum 25OHD (23 nmol/liter, 9 ng/ml). They were treated with vitamin D3, 60,000 IU/wk for 8 wk and then monthly together with calcium 1000 mg/d (18). Serum 25OHD reached 95 nmol/liter at 3 months and 56 nmol/liter (22 ng/ml) at 6 months. They found a significant improvement in grip strength, gastrocnemius strength, and the 6-min walking test by the end of study. But it is not known whether strength values at baseline were abnormal, and the numbers were small. Also, the treatment was vitamin D and calcium, compared with calcium alone and not placebo, which leaves some degree of uncertainty about the true effects of vitamin D on muscle. Could it be a calcium effect? In summary, there is no evidence that vitamin D treatment produces any significant improvement in muscle strength in elderly women with serum 25OHD levels that start at approximately 20 ng/ml and increase to 30 ng/ml, but in two of three studies with 25OHD levels below 50 nmol/liter, there was a significant improvement in muscle strength.

This brings us to the paper in this month's issue of the JCEM by Goswami et al. (21) from India. This group had previously shown a significant effect of vitamin D in young adults with very low 25OHD levels as described above (18). Although it was a positive study, they decided to repeat it with larger numbers and an improved study design that looked independently at calcium or vitamin D to confirm their original observations. This is an important study because aging was not a factor, and it is an opportunity to study the effect of vitamin D on people with very low levels of serum 25OHD.

A total of 173 young Indian ladies (average age, 22 yr) with very low levels of serum 25OHD (mean, 9.3 ng/ml) were randomized to one of four groups: calcium 500 mg twice daily, vitamin D, calcium + vitamin D, and placebo (21). Vitamin D was given at 60,000 IU/wk for 8 wk, and then every 2 wk for 6 months. Mean serum 25OHD was 9.3 ng/ml at baseline and increased to approximately 28 ng/ml in the two vitamin D-treated groups and was unchanged in the calcium or placebo groups. At 6 months, there were no significant differences in handgrip strength between the four groups, no difference in the 6-min walking test, and no difference in the quality of life assessment. Post hoc analyses based on serum 25OHD levels below or above 10 ng/ml were not different from the overall results. This is an interesting result because it took markedly vitamin D-deficient young women, treated them adequately, and found no improvement in any muscle function tests. In fact, the results are similar to those reported in many other studies, and as shown in the recent meta-analysis of vitamin D with or without calcium, there was no consistent effect on muscle strength (20).

The claim that vitamin D can increase muscle strength and function, as suggested in The Endocrine Society Guidelines in 2011, is clearly not tenable from the data available, and the claim that improved muscle strength on vitamin D reduces the incidence of falls is open to question (22). It was also suggested that vitamin D improved muscle strength by binding to a vitamin D receptor (VDR) in muscle, but recent data even cast doubt on this finding because recently, highly specific antibodies were unable to show the presence of a VDR in muscle (23), and it is likely that previous positive results were due to nonspecific binding because immunostaining for the VDR was positive in a VDR knockout animal. Moreover, reanalysis of the “fall data” by the Institute of Medicine showed that the meta-analysis had been performed incorrectly (24). It is still not clear whether vitamin D can reduce falls because of a lack of adequately powered studies, and if there is an effect, it could be through an action on calcium transport in muscle cells.

There is a marked decrease in muscle strength in the elderly that can be explained by a decrease in lean body mass (25, 26); less muscle equals less strength. The elderly also show changes in vitamin D metabolism; after age 75–80 yr, there is a decrease in 1,25-hydroxyvitamin D production by the aging kidney, and this can affect calcium transport into muscle cells. One possible explanation for the failure of vitamin D to increase muscle strength in the studies discussed above was that the active hormone serum 1,25-dihydroxyvitamin D was normal because serum 25OHD started at approximately 50 nmol/liter or 20 ng/ml. Usually, serum 1,25-dihydroxyvitamin D does not decrease until serum 25OHD is less than 10 ng/ml (27). In the present study by Goswami et al. (21), there was no increase in serum 1,25-dihydroxyvitamin D despite a large increase in serum 25OHD. In the one positive study of vitamin D on muscle strength from Japan, where serum 25OHD increased from 9.8 to 33 ng/ml, there was a significant increase in serum 1,25-dihydroxyvitamin D from 22 to 33 pg/ml and no change on placebo, and this occurred in an elderly population with aging kidney function and less ability to make 1,25-dihydroxyvitamin D in the presence of vitamin D deficiency. Two studies support the effect of 1,25-hydroxyvitamin D; one was a 3-yr placebo-controlled study with 1,25-hydroxyvitamin D that improved physical performance tests (SPPB), especially in those with a creatinine clearance below 60 ml/min (29), and the other was an open study that used 1α-dihydroxyvitamin D in 237 subjects in Germany and showed an improvement in SPPB tests at 6 months in patients with low creatinine clearance of approximately 50 ml/min, supporting the pivotal role of 1,25-hydroxyvitamin D (28).

In summary, treatment with vitamin D or 1,25-dihydroxyvitamin D may vary depending on the selection of the study group and their baseline level of 25OHD. In future studies, there should be better definition of the vitamin D axis. The present study in this month's issue of the JCEM adds some light to this issue. The young may be able to compensate when serum 25OHD levels are below 20 nmol/liter (10 ng/ml) because of secondary hyperparathyroidism and efficient production of 1,25-hydroxyvitamin D by a normal kidney. The elderly are less able to compensate because more than half have a marked decrease in renal function (glomerular filtration rate <60 ml/min) that leads to impaired 1,25-hydroxyvitamin D production and does not respond to the secondary hyperparathyroidism. Measuring the change in both serum 1,25-hydroxyvitamin D and 25OHD should be a goal in future studies of this important problem of decreased physical performance with aging.