Vitamin D and Muscle Function

Abstract

The aim of this review is to summarize current knowledge on the relation between vitamin D and muscle function. Molecular mechanisms of vitamin D action on muscle tissue have been known for many years and include genomic and non-genomic effects. Genomic effects are initiated by binding of 1,25-dihydroxyvitamin D3 (1,25(OH)2D) to its nuclear receptor, which results in changes in gene transcription of messenger RNA and subsequent protein synthesis. Non-genomic effects of vitamin D are rapid and mediated through a membrane-bound vitamin D receptor (VDR). Genetic variations in the VDR and the importance of VDR polymorphisms in the development of osteoporosis are still a matter of controversy and debate. Most recently, VDR polymorphisms have been described to affect muscle function. The skin has an enormous capacity for vitamin D production and supplies the body with 80-100% of its requirements of vitamin D. Age, latitude, time of day, season of the year and pigmentation can dramatically affect the production of vitamin D in the skin. Hypovitaminosis D is a common feature in elderly people living in northern latitudes and skin coverage has been established as an important factor leading to vitamin D deficiency. A serum 25-hydroxyvitamin D level below 50 nmol/l has been associated with increased body sway and a level below 30 nmol/l with decreased muscle strength. Changes in gait, difficulties in rising from a chair, inability to ascend stairs and diffuse muscle pain are the main clinical symptoms in osteomalacic myopathy. Calcium and vitamin D supplements together might improve neuromuscular function in elderly persons who are deficient in calcium and vitamin D. Thus 800 IU of cholecalciferol in combination with mg of elemental calcium reduces hip fractures and other non-vertebral fractures and should generally be recommended in individuals who are deficient in calcium and vitamin D. Given the strong interdependency of vitamin D deficiency, low serum calcium and high levels of parathyroid hormone, however, it is difficult to identify exact mechanisms of action.

Full text

Review Article
Vitamin D and Muscle Function
M. Pfeifer, B. Begerow and H. W. Minne
Institute of Clinical Osteology ‘Gustav Pommer’ and Clinic ‘Der Fu
¨
rstenhof’, Bad Pyrmont, Germany
Abstract. The aim of this review is to summarize current
knowledge on the relation between vitamin D and
muscle function. Molecular mechanisms of vitamin D
action on muscle tissue have been known for many years
and include genomic and non-genomic effects. Genomic
effects are initiated by binding of 1,25-dihydroxyvitamin
D
3
(1,25(OH)
2
D) to its nuclear receptor, which results in
changes in gene transcription of messenger RNA and
subsequent protein synthesis. Non-genomic effects of
vitamin D are rapid and mediated through a membrane-
bound vitamin D receptor (VDR). Genetic variations in
the VDR and the importance of VDR polymorphisms in
the development of osteoporosis are still a matter of
controversy and debate. Most recently, VDR polymorph-
isms have been described to affect muscle function. The
skin has an enormous capacity for vitamin D production
and supplies the body with 80–100% of its requirements
of vitamin D. Age, latitude, time of day, season of the
year and pigmentation can dramatically affect the
production of vitamin D in the skin. Hypovitaminosis
D is a common feature in elderly people living in
northern latitudes and skin coverage has been established
as an important factor leading to vitamin D deficiency. A
serum 25-hydroxyvitamin D level below 50 nmol/l has
been associated with increased body sway and a level
below 30 nmol/l with decreased muscle strength.
Changes in gait, difficulties in rising from a chair,
inability to ascend stairs and diffuse muscle pain are the
main clinical symptoms in osteomalacic myopathy.
Calcium and vitamin D supplements together might
improve neuromuscular function in elderly persons who
are deficient in calcium and vitamin D. Thus 800 IU of
cholecalciferol in combination with 1200 mg of
elemental calcium reduces hip fractures and other non-
vertebral fractures and should generally be recom-
mended in individuals who are deficient in calcium
and vitamin D. Given the strong interdependency of
vitamin D deficiency, low serum calcium and high levels
of parathyroid hormone, however, it is difficult to
identify exact mechanisms of action.
Keywords: Body sway; Falls; Muscle function; Non-
vertebral fractures; Vitamin D
Introduction
Although possible interactions between vitamin D status
and muscle function have been known for decades, only
a few clinical trials have been performed in this field.
The aim of this review is to summarize the molecular
and clinical perspective of vitamin D action on muscle
function in the light of recently published studies
investigating the effects of vitamin D and/or calcium
treatment on parameters of muscle function or falls.
Starting with molecular aspects and vitamin D metabo-
lism, reasons and consequences of vitamin D deficiency
and the additional role of parathyroid hormone are
described. Finally, the effects of vitamin D and calcium
supplementation are discussed to open new insights into
the extraskeletal factors related to vitamin D.
Molecular Aspects
Molecular mechanisms of action of 1,25-dihydroxyvita-
min D
3
(1,25(OH)
2
D) and other vitamin D metabolites
include genomic and non-genomic effects [1]. Genomic
effects on the classical target organs bone, skeletal
muscle, parathyroid glands, intestine and kidney have
Osteoporos Int (2002) 13:187–194
ß 2002 International Osteoporosis Foundation and National Osteoporosis Foundation
Osteoporosis
International
Correspondence and offprint requests to: Dr Michael Pfeifer, Institute
of Clinical Osteology ‘Gustav Pommer’ and Clinic ‘Der Fu
¨
rstenhof’,
Am Hylligen Born 7, G-31812 Bad Pyrmont, Germany. Tel: +49 5281
151414. Fax: +49 5281 151100. e-mail: iko_pyrmont@t-online.de

been known for many years. These effects of
1,25(OH)
2
D facilitate the calcification of bone matrix
and include an increased absorption of Ca
2+
and
phosphate from the intestine, and increased reabsorption
of Ca
2+
in the kidney [2]. In addition to these vital
calcemic actions, the discovery of the nuclear receptor of
1,25(OH)
2
D opened the possibility that vitamin D might
exert variable non-calcemic actions [3]. In the meantime,
vitamin D receptors have been demonstrated in most
‘non-classical’ target tissues of the body including
smooth muscle, heart muscle, thyroid, cells of the
immune system, brain, liver, lung, colon, gonads,
prostate, skin and others [4].
Genomic effects are initiated by binding of
1,25(OH)
2
D to its nuclear receptor, which results in
changes in the gene transcription of mRNA and
subsequent de novo protein synthesis [3]. Recently,
genetic variations in the vitamin D receptor (VDR) and
the importance of the VDR polymorphisms in the
development of osteoporosis have been of increasing
interest [5]. Furthermore, there is some evidence from
Geusens et al. [6] that VDR polymorphisms may affect
muscle function. These authors found a 23% difference
in quadriceps strength (p50.01) between the bb and BB
genotype of the VDR in nonobese women 70 years of
age or older [6].
Non-genomic effects of vitamin D are rapid and
mediated through a membrane-bound VDR [7]. The
binding to the receptor initiates a cascade leading to the
formation of a second messenger (cAMP, diacylglycerol,
inositol triphosphate, arachidonic acid) or phosphoryla-
tion of intracellular proteins. Non-genomic actions of
vitamin D have been well described in muscle; their
significance, however, is still a matter of debate [8].
Vitamin D Metabolism
The secosteroid hormone vitamin D is produced in the
skin after exposure to UVB radiation (290–315 nm) [9].
The skin has an enormous capacity for vitamin D
production and supplies the body with 80–100% of its
requirements for vitamin D [10]. It is uncertain whether
vitamin D
2
, which comes from yeasts and plants, and
vitamin D
3
, which is found in fatty fish and is made in
the skin, have the same biologic potency in humans,
since vitamin D
2
may be converted less to 1,25(OH)
2
D
than is vitamin D
3
. Vitamin D is biologically inert and
must undergo two successive hydroxylations in the liver
and kidney to become the biologically active
1,25(OH)
2
D [11]. The 25-hydroxylation in the liver is
very fast and almost unregulated. Serum 25-hydroxyvi-
tamin D (25OHD), therefore, reflects either cutaneous
production in the skin or dietary intake, and can be used
as a marker for vitamin D status [10,11]. On the other
hand, the formation of 1,25(OH)
2
D in the kidney is
tightly regulated by parathyroid hormone and – as a
negative feedback regulation – by 1,25(OH)
2
D itself.
Other regulators include calcium, phosphate, growth
hormone and prolactin [9,11].
The VDR has a 500- to 1000-fold higher affinity for
1,25(OH)
2
D than 25OHD, but as the serum concentra-
tion of 25OHD is about 500 times higher than that of
1,25(OH)
2
D, biological activity of 25OHD cannot be
ruled out. Both 25OHD and 1,25(OH)
2
D undergo a 24-
hydroxylation to form 24,25(OH)
2
D and 1,24,25(OH)
3
D,
respectively [9]. These metabolites are the first step in
the biodegradation which ends, after several hydroxyla-
tions, with the formation of water-soluble calcitroic acid.
Although more than 40 different metabolites of vitamin
D have been identified, only 1,25(OH)
2
D is believed to
be important for most of the biologic actions of vitamin
D [9,11].
Hypovitaminosis D
Age, latitude, time of day, season of the year and
pigmentation can dramatically affect the production of
vitamin D in the skin [9]. Compared with a young adult,
a person older than 70 years produces less than 30% of
the amount of vitamin D when exposed to the same
amount of sunlight [12]. At a latitude of 428 N (Boston,
MA, USA), sunlight is incapable of producing vitamin D
in the skin between the months of November and
February. At 528 N (Edmonton, Canada) this period is
extended to include the months of October through
March [13]. These figures illustrate why hypovitami-
nosis D is a common feature in elderly people living in
northern latitudes. Among 290 consecutive patients on a
general ward in Boston, a total of 164 (57%) were
considered vitamin D deficient (serum 25OHD below 15
ng/ml or 37.5 nmol/l) [14]. Chapuy et al. [15] found that
the prevalence of vitamin D insufficiency in the general
adult urban French population was highest (31%) in the
North (latitude 518 N) and lowest (7%) at the
Mediterranean coast (latitude 438 N) [15]. In an Italian
study performed in the Milan area, 51% of free-living
women 70 years of age or older were considered vitamin
D deficient (serum 25OHD below 12 ng/ml) during
wintertime (December–May), while 17% had deficient
vitamin D levels in the period June–November [16]. A
recently published study from Madrid, Spain demon-
strated that the prevalence of vitamin D deficiency
(serum 25OHD below 37.5 nmol/l) among postmeno-
pausal women (aged 47–66 years) from a rheumatologic
outpatient clinic was 64% [17]. The authors of this study
concluded that skin coverage may be as important as
latitude with regard to hypovitaminosis D [17].
The concept of vitamin D ‘insufficiency’, which has a
biologic effect on calcium homeostasis and skeletal
metabolism, needs to be distinguished from both vitamin
D ‘deficiency’, which leads to osteomalacia, and vitamin
D ‘sufficiency’, which has no effect on calcium
homeostasis [18]. The threshold of the serum 25OHD
concentration that separates vitamin D sufficiency from
insufficiency can be defined by the biologic effects of the
latter, in particular the increase in plasma parathyroid
hormone (PTH) levels and the conversion of 25OHD to
1,25-(OH)
2
D. Chapuy et al. [15] found such an increase
188 Vitamin D and Muscle Function

in plasma PTH levels when the serum 25OHD value was
lower than 78 nmol/l (31 ng/ml).
The increased secretion in PTH in vitamin D
insufficiency is well documented [19,20], and contri-
butes to bone fragility, and probably to bone fractures, in
the elderly through increased bone turnover and
decreased bone density [21–23]. Serum 25OHD levels
below 30 nmol/l (12 ng/ml) are associated with
secondary hyperparathyroidism, increased bone turnover
and decreased bone mineral density (BMD) at the hip
[22]. As described in the Danish study of Glerup et al.
[24], a serum 25OHD level below 20 nmol/l had been
associated with severely impaired muscle function in
veiled Arab women. This effect of hypovitaminosis D on
muscle function has been confirmed by Bischoff et al.
[25], who found a lower muscle strength in men and
women with a serum 25OHD level below 30 nmol/l.
Osteomalacic Myopathy
Muscular weakness and hypotonia have been described
as characteristic symptoms in infants with vitamin D
deficient rickets [26]. In older children the weakness
may be present as a proximal myopathy and in adults
diffuse skeletal pain and muscular weakness may be
present in the absence of a specific pattern. Pain is often
prominent about the hips and may produce a waddling
gait [27]. Besides changes in gait, clinical findings in
osteomalacic myopathy include proximal muscle weak-
ness – predominantly extension, flexion and abduction of
the hip and flexion and extension of the knee – as well as
difficulties in rising from a chair, inability to ascend
stairs [28] and diffuse muscle pain [29].
Skaria et al. [30] reported in 1975 that 25 of 30
patients with proven osteomalacia showed an abnormal
electromyogram with signs of both myopathy and
reduced nerve conduction velocity. Fourteen patients
were followed during vitamin D treatment for several
months and 93% showed improvement in their electro-
myogram, but not in the nerve conduction velocity [30].
The involvement of peripheral nerves in the disease is
reported by some investigators [30,31], while others
describe a normal nerve conduction velocity [32].
Muscle biopsies obtained in osteomalacic patients
reveal an atrophy of type II muscle fibers with enlarged
interfibrillar spaces and infiltration of fat, fibrosis and
glycogen granules [33]. In neuropathic atrophy, typically
type I and type II fibers are affected, while in
immobilization atrophy only type I fibers are reduced
[34]. In sudden movements, the fast and strong type II
fibers are the first to be recruited to avoid falling [35].
Thus, the fact that primarily type II fibers are affected by
vitamin D deficiency probably explains the falling
tendency of vitamin D deficient elderly individuals
[1,36,37].
The understanding of the importance of vitamin D for
muscle function was improved by Curry et al. [38], who
demonstrated that the ATP-dependent Ca
2+
uptake of
isolated vesicles in sarcoplasmic reticulum was reduced
in muscles of vitamin D depleted rabbits compared with
repleted animals [38]. These findings were reversed by
pretreatment with vitamin D [38]. In another in vivo
model of vitamin D depleted and repleted rats, Rodman
and Baker [39] observed a prolonged time to peak and
relaxation half-life in vitamin D depleted animals, which
could be normalized by vitamin D treatment prior to the
experiment. In an in vitro model, Birge and Haddad [40]
found that 25OHD increased the intracellular content of
ATP and phosphate and increased protein synthesis.
Furthermore, they demonstrated the presence of an
intracellular protein with high affinity for both 25OHD
and actin [41]. This protein, which was later identified as
vitamin D binding protein (DBP), has been proposed to
be a mediator of the effects of 25OHD in muscle.
1,25(OH)
2
D seems to be responsible for the active
transportation of Ca
2+
into sarcoplasmatic reticulum
(SR) by Ca-ATPase [42]. Thereby, the activity of the Ca-
ATPase is regulated by 1,25(OH)
2
D-stimulated phos-
phorylation of proteins in the SR membrane [41]. In
vitamin D depleted animals, the content of actin and
troponin C, which are important contractile proteins in
the muscle cell, has been demonstrated to be reduced
[43]. This content has been normalized by vitamin D
treatment, which seems to be an action of 25OHD rather
than 1,25(OH)
2
D [43,44]. Thus vitamin D has an
important role in the regulation of Ca
2+
transport and
protein synthesis in the muscle cell. Vitamin D increases
the calcium pool, which is essential for muscle
contraction. These effects are mediated by the nuclear
vitamin D receptor, as was demonstrated more than 10
years ago [45], and by a variety of non-genomic effects,
which are, however, of unclear significance.
Role of Parathyroid Hormone
Fatigue and muscular weakness have been described as
prominent clinical symptoms in patients with primary
hyperparathyroidism (pHPT) [46]. After successful
surgery, a significant improvement in these muscular
symptoms can be observed [46,47]. In addition, muscle
biopsies obtained in patients suffering from pHPT,
reveal atrophy of type II muscle fibers [48].
Parathyroid hormone (PTH) increases the proteolysis
of muscle proteins and thereby augments the liberation
of the amino acids alanine and glutamine [49].
Treatment with PTH reduces the intracellular content
of inorganic phosphate, creatine phosphate and Ca-
ATPase in rat muscle cells [50]. Furthermore, mitochon-
drial oxygen consumption and the activity of creatine
phosphokinase and Ca-ATPase were reduced. In
addition, PTH impairs the oxidation of long-chain fatty
acids in skeletal muscle [51].
Thus many parallels exist between the muscular
effects of hypovitaminosis D and primary hyperpar-
athyroidism. In osteomalacic myopathy vitamin D
deficiency as well as an excess of PTH exist and
therefore it is most likely that both factors contribute to
the pathogenesis of myopathy. On the other hand,
M. Pfeifer et al. 189

however, while PTH may contribute to myopathy, a high
calcium intake may correct myopathy because it
suppresses PTH secretion [52]. It is well known that a
high calcium intake may compensate the effects of
vitamin D deficiency to a certain degree. More research
is needed to define the exact roles of vitamin D and PTH
in the regulation of muscle function.
Therapeutic Implications
Supplementation with vitamin D (800 IU/day) and
calcium (1200 mg/day) led to a 43% reduction in hip
fracture risk among nursing home residents after 18
months of treatment [53]. This figure, however, is the
best estimate at one time point and was reduced to 25%
after a 3-year study period [54]. The bone density at the
proximal femur increased by 2.7% in the vitamin D–
calcium group and decreased by 4.6% in the placebo
group [53]. An analysis of a random subset of 248
nonindependent-living women, selected from a larger
trial consisting of independent and nonindependent-
living Dutch men and women, showed a 2.2% increase
in femoral neck BMD in the group that received 400 IU
per day of vitamin D compared with the control group
[23]. In addition, in men and women 65 years of age or
older living in the community, dietary supplementation
with vitamin D and calcium moderately increased BMD
measured at the femoral neck (placebo: –0.70  5.03%;
Ca
2+
and vitamin D: +0.50  4.80%; p = 0.02) and spine
(placebo: +1.22  4.25%; Ca
2+
and vitamin D: +2.12 
4.06%; p = 0.04) [55]. However, despite these relatively
small increases in BMD, a significant reduction in the
incidence of non-vertebral fractures was observed in this
study [55]. Twenty-six subjects in the placebo group
compared with 11 subjects in the Ca
2+
/vitamin D group
had non-vertebral fractures (p = 0.02) [55]. This
corresponds to the findings by Heikinheimo et al. [56],
who reported a significant reduction in upper limb
fractures after a single annual injection of ergocalciferol.
With regard to vitamin D monotherapy, however, Lips
et al. [57] found no impact on hip or peripheral fracture
risk in a large 3.5-year trial of 2578 men and women
aged 70 years and older [57]. This study might have
shown a negative result because of the lower dose of
vitamin D used (400 IU), or the less marked secondary
hyperparathyroidism that occurred in the subjects [57].
Furthermore, all subjects received written direction to
consume 800–1000 mg per day of calcium and were,
therefore, probably not calcium-deficient.
From these results it seems unlikely that the anti-
fracture efficacy of vitamin D and Ca
2+
is attributable to
their effect on bone density alone. Supplementation with
vitamin D and calcium decreased secondary hyperpar-
athyroidism and decreased bone turnover [55]. Conse-
quently, the effect of vitamin D and calcium on non-
vertebral fractures could be the result of an increase in
bone strength.
Another explanation for the observed reduction in
fracture risk could be an effect of vitamin D and calcium
on the risk of falling. We have found in a prospective,
randomized, placebo-controlled trial that short-term
supplementation with vitamin D and calcium reduced
body sway and the mean number of falls during a 1-year
period of follow-up in women 70 years of age or older
who were vitamin D deficient (mean serum 25OHD
level: 23 nmol/l) with a mean calcium intake of 560 mg
per day and living at a latitude of 528 N [58]. The
women received either 1200 mg of elemental calcium or
1200 mg of elemental calcium and 800 IU of
cholecalciferol per day. Compared with calcium mono-
therapy, supplementation with vitamin D and calcium in
women with vitamin D insufficiency resulted in a
decrease in plasma PTH of 18% (p = 0.0435), and a
decrease in body sway of 9% (p = 0.0435). The mean
number of falls during 1 year of double-masked follow-
up was 0.47 for the calcium monotherapy group and 0.24
for the vitamin D and calcium group (p = 0.0346) [58].
These results support the concept that hypovitaminosis D
impairs neuromuscular coordination, as measured by
body sway, and thus increases the risk of falling and fall-
related fractures. This is also supported by Stein et al.’s
[37] demonstration of lower serum 25OHD and higher
serum PTH levels in ambulant nursing home and hotel
residents (mean age 84 years) who fell compared with
non-fallers.
Concerning muscle strength, Bischoff et al. [25]
described a relation between loss of muscle strength
and vitamin D deficiency in ambulatory elderly men and
women in a cross-sectional study. In men (mean age 77
years) both 25OHD and 1,25(OH)
2
D were significantly
correlated with leg extension power (LEP) (r = 0.24,
p50.001 and r = 0.14, p = 0.045), whereas in women
(mean age 74 years) only 1,25(OH)
2
D was significantly
correlated with LEP (r = 0.22, p = 0.034) [25]. In a
randomized, controlled trial Bischoff et al. [59]
demonstrated a reduction in falls after treatment with
vitamin D and calcium in elderly institutionalized
women. The women, with a mean age of 85  7 years
received either 1200 mg of elemental calcium or 1200
mg of elemental calcium plus 800 IU of vitamin D.
Mean fall incidence rate – the number of falls before
treatment subtracted from the number of falls during
treatment period – was 2.7 in the calcium group and 1.1
in the calcium and vitamin D group (p50.01).
In veiled Arab women living in Denmark, Glerup et
al. [24] found that muscle power as determined by
maximal voluntary contraction (MVC) significantly
correlated with serum levels of 25OHD (r = 0.34,
p50.01) but not with 1,25(OH)
2
D(r = –0.14, NS) [24].
Compared with Danish controls, maximal voluntary
knee extension as measured with a strain gauge
dynamometer was reduced by 34% in 55 vitamin D
deficient Arab women (serum 25OHD 520 nmol/l).
Treatment with intramuscular injections of ergocalcifer-
ol 100 000 IU per month and an oral supplementation of
1200 mg calcium and 400 IU ergocalciferol per day
resulted in an increase in mean MVC of 13% after 3
months and 24% after 6 months [24].
190 Vitamin D and Muscle Function

In another treatment study, Grady et al. [60] failed to
demonstrate any muscular effects of treatment with 0.5
mg calcitriol daily in 98 men and women volunteers over
69 years old. Serum levels of 25OHD among the
participants were, however, above 460 nmol/l [60]. If
25OHD is the primary in vivo mediator, no hypovita-
minosis D myopathy could be expected among these
participants, and consequently no effect of treatment
with calcitriol should be expected. Graafmans et al. [61]
determined intrinsic risk factors for falls among 354
elderly subjects aged 70 years or over who were living in
homes or apartments for the elderly in The Netherlands.
Although impairment of balance, leg extension strength
and gait were strongly associated with falls in this
prospective, randomized study, the use of vitamin D,
which was randomly allocated to the participants, was
not strongly related to falls. However, vitamin D status
at baseline had not been documented and the dose of
vitamin D (400 IU) might have been to low. The clinical
trials of treatment with vitamin D that used parameters
of muscle function and/or falls as end-points are
summarized in Table 1.
Muscle weakness is common among vitamin D
deficient individuals (serum 25OHD 530 nmol/l).
Reduced function of the faster and stronger type II
fibers could result in increased frequency of falls,
leading to increased incidence of non-vertebral fractures.
There is some evidence that body sway – as an early
marker for hypovitaminosis D related myopathy – is
impaired in subjects with 25OHD levels below 50 nmol/l
[58]. This mechanism could represent a satisfactory
explanation for the reduced incidence of non-vertebral
fractures [53,54] and falls [58,59,62] seen in elderly
individuals who took vitamin D prophylactics. If patients
are calcium and vitamin D deficient, a supplement of 800
IU of cholecalciferol in combination with 1200 mg of
elemental calcium should be generally recommended.
Vitamin D and Vascular Smooth Muscle
In addition to striated muscle, vascular smooth muscle is
also a target organ for vitamin D [62]. 1,25(OH)
2
D has
been shown to increase active stress generation by
enhancing intracellular Ca
2+
mobilization in resistance
arteries of rats [63]. Furthermore, 1,25(OH)
2
D increases
active stress generation by a myosin light chain
phosphorylation-dependent mechanism and an increas-
ing myofilament Ca
2+
sensitivity [64]. Consequently, an
association of 1,25(OH)
2
D and blood pressure has been
demonstrated in normotensive men [65], myocardial
infarction was inversely associated with plasma 25OHD
levels in a community-based study [66], and higher
blood pressure in elderly women correlated with
increased bone loss in a recently published prospective
study [67]. St John et al. [68] investigated the relation-
ship between calcitropic hormones and blood pressure in
583 elderly subjects who were untreated for hyperten-
sion but who were not vitamin D deficient. Multivariate
analysis in this study demonstrated that both PTH and
1,25(OH)
2
D were significant independent determinants
of blood pressure [68].
In a prospective, randomized and double-masked
clinical trial we observed a decrease in systolic blood
pressure of 9.3% (p = 0.02) and a decrease in heart rate
of 5.4% (p = 0.02) after short-term vitamin D (800 IU/
day) and calcium (1200 mg/day) supplementation in
women 70 years of age or older with a serum 25OHD
level below 50 nmol/l [69].
Open Questions
The clinical effects of vitamin D on striated muscle seem
to be related more to 25OHD than to 1,25(OH)
2
D. There
are two studies available indicating an important effect
of 25OHD on muscle protein synthesis [40,43], but there
Table 1. Clinical trials of treatment with vitamin D that used parameters of muscle function and/or falls as end-points
Study/Year Treatment Dose Subjects Age
a
Duration
b
Comments
Grady et al. [60]
(1991)
Calcitriol 0.5 mg/day 98 men and women 69 6 No effect on muscle strength
probably due to high serum
25OHD levels (460 nmol/l)
Graafmans et al. [61]
(1996)
Cholecalciferol 400 IU/day 354 men and women living
in homes for the elderly
>70 7 No effect on falls possibly due
to low dose of vitamin D
and/or less marked secondary
hyperparathyroidism
Glerup et al. [24]
(2000)
Ergocalciferol
i.m./month
c
100 000 IU 55 veiled Arab women,
25OHD
d
= 6.7 nmol/l
32 6 Significant improvement of
maximal voluntary knee
extension
Pfeifer et al. [58]
(2000)
Cholecalciferol 800 IU/day 148 ambulatory women,
25OHD
d
= 23 nmol/l
74 2 Significant decrease in body
sway and number of falls
during 1 year of follow-up
Bischoff et al. [59]
(2001)
Cholecalciferol 800 IU/day 122 institutionalized women,
25OHD
d
= 12 nmol/l
84 6 Significant decrease in fall
incidence rate and improvement
of functional measures
a
Mean age of study participants in years.
b
Duration of treatment period in months.
c
Intramuscular injection of ergocalciferol 100 000 IU per month and an oral supplementation of 400 IU per day.
d
Serum 25-hydroxyvitamin D level at baseline.
M. Pfeifer et al. 191

is still a strong need for more experimental studies on the
cellular effects of 25OHD. Furthermore, the relative
contribution of 1,25(OH)
2
D to the clinical picture of
osteomalacic myopathy is unclear. In patients with
primary hyperparathyroidism muscle symptoms occur
which are like the symptoms seen in hypovitaminosis D
myopathy due to nutritional vitamin D deficiency or
renal insufficiency. Thus the role of PTH in muscle
function waits to be defined. In addition, the fundamental
problem of interference and the relative contribution of
vitamin D deficiency and low serum calcium in
explaining altered muscle function cannot be solved
with the present clinical studies, since calcium and
vitamin D status are strongly interdependent and a high
calcium intake may compensate the effects of vitamin D
deficiency to a certain degree. Furthermore, it is unclear
whether the blood pressure lowering effect of a vitamin
D and calcium supplementation is due more to a direct
influence of vitamin D on vascular smooth muscle, or to
a suppression of secondary elevated PTH.
There is some evidence that muscle-strengthening
exercise is associated with enhanced serum 1,25(OH)
2
D
levels [70] and exercise-trained young men have higher
calcium absorption rates and plasma calcitriol levels
compared with age-matched controls [71]. On the other
hand, in marathon runners elevated plasma calcitriol
levels were observed after a training break and a
decrease occurred after 2 and 4 weeks of retraining
[72]. Differences in calcitriol levels have also been
observed between endurance-trained and sedentary
postmenopausal women [73]. While treatment with
vitamin D and calcium in vitamin D deficient states is
associated with an increase in muscle strength, the
reverse – an increase in serum 1,25(OH)
2
D after muscle-
strengthening exercise – seems to be plausible but needs
to be further investigated.
Conclusion
There is some evidence from results of recently
published studies to support the idea that calcium and
vitamin D deficiency alters muscle function and thus
increases the risk for falls. On the other hand,
supplementation with calcium and vitamin D may
improve muscle function and reduce the risk for falling
in individuals deficient in calcium and vitamin D. Given
the strong interdependency of vitamin D deficiency and
low serum calcium with high serum levels of parathyroid
hormone, however, further research is needed to identify
exact mechanisms of action.
Note Added in Proof
In a large clinical multi-center study, Flicker et al.
identified the serum 25(OH)D level as a major risk factor
for falls in 4251 older women (mean age 84 years) living
in two types of residential care in Melbourne and Perth,
Australia. Among other risk factors, like past Colles
fracture, neuroleptic use, walking with a frame and
mental impairment, a Cox proportional hazard model
revealed for natural log 25(OH)D a hazard ratio for falls
of 0.64 (95% CI 0.47–0.89; p = 0.004). This indicates
that serum vitamin D levels are independently and
inversely associated with falls in women in residential
care even after adjustment for other risk factors (Flicker
L, Mead K, Nowson C et al. Risk factors for falls in
older women in residential care in Australia [abstract]. J
Bone Miner Res 2001;16(Suppl 1):S170).
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Received for publication 30 March 2001
Accepted in revised form 20 September 2001
194 Vitamin D and Muscle Function