Cã¡Ch Sá»­ DụNg Vitamin D

Cã¡Ch Sá»­ DụNg Vitamin D

The Roles of Vitamin D in Skeletal Muscle: Form, Function, and Metabolism

Christian M. Girgis,

1Garvan Institute of Medical Research (C.M.G., J.E.G.), University of New South Wales, Sydney, New South Wales 2010, Australia;

2Faculty of Medicine (C.M.G., R.J.C.-B., J.E.G.), University of Sydney, Sydney, New South Wales 2052, Australia;

*Address requests for reprints to: Dr. Christian M. Girgis or Associate Professor Jenny E. Gunton, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales, Australia.

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Roderick J. Clifton-Bligh,

Roderick J. Clifton-Bligh

2Faculty of Medicine (C.M.G., R.J.C.-B., J.E.G.), University of Sydney, Sydney, New South Wales 2052, Australia;

3The Kolling Institute of Medical Research (R.J.C.-B.) and Royal North Shore Hospital (R.J.C.-B.), Sydney, New South Wales 2065, Australia;

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Mark W. Hamrick,

4Georgia Health Sciences University (M.W.H.), Augusta, Georgia 30912;

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Michael F. Holick,

5Boston University Medical Center (M.F.H.), Boston, Massachusetts 02118;

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Jenny E. Gunton

1Garvan Institute of Medical Research (C.M.G., J.E.G.), University of New South Wales, Sydney, New South Wales 2010, Australia;

2Faculty of Medicine (C.M.G., R.J.C.-B., J.E.G.), University of Sydney, Sydney, New South Wales 2052, Australia;

6Department of Endocrinology and Diabetes (J.E.G.), Westmead Hospital, Sydney, New South Wales 2145, Australia

7St. Vincent's Clinical School (J.E.G.), University of New South Wales, Sydney, New South Wales 2010, Australia;

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Received:

28 February 2012

Published:

01 February 2013

Abstract

Beyond its established role in bone and mineral homeostasis, there is emerging evidence that vitamin D exerts a range of effects in skeletal muscle. Reports of profound muscle weakness and changes in the muscle morphology of adults with vitamin D deficiency have long been described. These reports have been supplemented by numerous trials assessing the impact of vitamin D on muscle strength and mass and falls in predominantly elderly and deficient populations. At a basic level, animal models have confirmed that vitamin D deficiency and congenital aberrations in the vitamin D endocrine system may result in muscle weakness. To explain these effects, some molecular mechanisms by which vitamin D impacts on muscle cell differentiation, intracellular calcium handling, and genomic activity have been elucidated. There are also suggestions that vitamin D alters muscle metabolism, specifically its sensitivity to insulin, which is a pertinent feature in the pathophysiology of insulin resistance and type 2 diabetes. We will review the range of human clinical, animal, and cell studies that address the impact of vitamin D in skeletal muscle, and discuss the controversial issues. This is a vibrant field of research and one that continues to extend the frontiers of knowledge of vitamin D's broad functional repertoire.

• I.

  Introduction

• II.

  Background Physiology

  • A.

    The vitamin D pathway

  • B.

    Skeletal muscle physiology

  • C.

    Calcium and muscle contraction

  • D.

    Calcium and exercise-related glucose uptake

  • E.

    Calcium and insulin-stimulated glucose uptake

• III.

  Vitamin D and Muscle: Cell Models

  • A.

    VDR in muscle

  • B.

    Calcium homeostasis

  • C.

    Phosphate homeostasis

  • D.

    Proliferation and differentiation

  • E.

    Muscle contractile proteins

  • F.

    Phospholipid composition

  • G.

    Bone-muscle cross talk and vitamin D

  • H.

    Cell models and molecular pathways for insulin signaling and diabetes

• IV.

  Vitamin D and Muscle: Studies in Animal Models

  • A.

    VDRKO mice

  • B.

    Other animal models

  • C.

    Animal studies on insulin sensitivity and diabetes

  • D.

    Summary: vitamin D and muscle function in animal studies

• V.

  VDR Polymorphisms and Muscle Function

  • A.

    FokI polymorphisms

  • B.

    BsmI polymorphisms

  • C.

    VDR polymorphisms and insulin resistance/type 2 diabetes

• VI.

  Vitamin D and Muscle: Human Studies

  • A.

    Myopathy

  • B.

    Myalgia and vitamin D deficiency

  • C.

    Fibromyalgia

  • D.

    Drug-related myopathy and vitamin D

  • E.

    Falls and vitamin D

  • F.

    Muscle strength and physical performance

  • G.

    Muscle morphology and electromyography (EMG)

  • H.

    Insulin sensitivity and glucose handling

• VII.

  Conclusions

I. Introduction

In recent times, there has been a great deal of interest in vitamin D, with over 1000 publications in PubMed in 2011 alone. A remarkable number of studies dealing with novel aspects of its biological activity and its potential to exert broad-ranging effects beyond calcium and mineral homeostasis have emerged (1–4). Vitamin D deficiency is a highly prevalent condition in the developed world and in the populous regions of Asia, India, and the Middle East (5, 6). Significant downward trends in vitamin D status in U.S. population-based studies suggest that vitamin D deficiency/insufficiency is increasing in frequency (7, 8). Accordingly, health agencies including the International Osteoporosis Foundation, The Endocrine Society, and Institute of Medicine have recently outlined recommendations for the prevention of vitamin D deficiency and have called for further research to guide the field (9–11).

Beyond the classic effects on bone and calcium health, the effects of vitamin D are a matter of considerable debate and have been recently reviewed in detail (12). A recent Institute of Medicine report contended that the evidence in support of an extraskeletal role for vitamin D was "not yet compelling" (11). However, there is a large and expanding body of observational data about associations between vitamin D deficiency and diverse medical conditions, ranging from multiple sclerosis to malignancy (3). Reports of the presence of the vitamin D receptor (VDR) in almost every tissue strengthen the case in favor of direct extraskeletal functions (13). The effective use of active vitamin D and vitamin D analogs in the treatment of the skin disorder, psoriasis, demonstrate that skin is an extraskeletal target tissue for vitamin D.

Long before the recognition of UV radiation as an essential component in the synthesis of vitamin D, the sun's rays were considered a source of physical strength and vitality. Ancient Egyptians revered the Sun-God, Amon-Rah, whose rays could make "a single man stronger than a crowd" (14). Herodotus recommended solaria in Ancient Greece as a cure for "weak and flabby muscles," and ancient Olympians were instructed to lie exposed and train under the sun's rays (15).

In 1952, Spellberg (16), a German sports physiologist, conducted an extensive study examining the effects of UV irradiation on elite athletes. He informed the German Olympic Committee that UV irradiation had a "convincing effect" on physical performance. This was consistent with earlier studies that reported improvements in speed and endurance among students after treatment with sunlamps (17, 18).

We have known for more than 30 yr that vitamin D exerts effects on muscle cells at a molecular level. In this journal in 1986, Ricardo Boland reviewed the effects of vitamin D on calcium handling, mineral homeostasis, and signaling pathways in muscle cells (19). Since that time, we have gained further insight in its effects on the regulation of cell survival (20), differentiation (21), and calcium handling (22). In more recent times, clinical studies have examined the effects of vitamin D supplementation on muscle function and falls in various populations (23, 24).

However, the field is challenged by controversy. A recent report suggesting that VDR was not detectable in muscle has fueled the debate as to whether vitamin D effects on muscle are direct or indirect (25–27). The creation of the VDR knockout (VDRKO) mouse in 1997 gave a new focus to this question, which we will discuss (28). A continuing area of uncertainty stems from conflicting meta-analyses of clinical studies examining the effect of vitamin D supplementation on muscle strength and falls in older individuals (23, 29–31).

In this review, molecular, animal, and human studies examining the various roles of vitamin D in muscle will be presented. We will discuss contentious issues that have made this a vibrant field of research and one that continues to extend the frontiers of our knowledge of vitamin D's broad functional repertoire.

II. Background Physiology

A. The vitamin D pathway

The family of molecules known collectively as vitamin D are not true vitamins, which are defined as essential substances obtained exclusively from the diet. The misnomer is a remnant of the early work of a number of scientific pioneers from the 1900s.

After inducing rickets in a group of dogs by keeping them indoors for prolonged periods, the British physician Sir Edward Mellanby (32) discovered that feeding them cod-liver oil cured them and attributed this to the recently identified vitamin A (33). However, in 1922, McCollum et al. (34) showed that after heating and aerating cod-liver oil to destroy the vitamin A, it remained effective in the treatment of rickets but no longer cured night blindness. McCollum followed the sequential alphabetical designations and labeled the new substance "vitamine D." In the 1920s, it was recognized that children with rickets had profound muscle weakness, and Alfred F. Hess (35) reported that exposing rachitic children to direct sunlight led to the "rapid disappearance" of their illness and improved "general vigor and nutrition." This finding was the direct extension of earlier work by Huldschinsky (36), who achieved the same outcome with artificially produced UV light.

After these seminal studies, Harry Goldblatt and Katherine Soames (37) reported in 1923 that the irradiation of certain foodstuffs rendered them antirachitic. In 1926, Adolf Windaus et al. (38) identified the chemical structure of cholecalciferol (vitamin D₃) as found in irradiated pig skin as well as the structure of its parent molecule, 7-dehydrocholesterol. Windaus also isolated vitamins D₁ and D₂ and was awarded the 1928 Nobel prize for his work on sterols and vitamins. The nomenclature in the field is often confusing. Names, alternate names, and molecular structures of vitamin D and related molecules are shown in Fig. 1. The metabolic pathway of vitamin D, including the various steps in its activation and degradation, are depicted in Fig. 2.

Figure 2.

Summary of the vitamin D pathway. Steps are discussed in the text. Molecular structures and alternate names for each of the compounds are found in Fig. 1.

Figure 2.

Summary of the vitamin D pathway. Steps are discussed in the text. Molecular structures and alternate names for each of the compounds are found in Fig. 1.

Figure 1.

Summary of the molecular structures and various names of vitamin D and its related compounds (molecular structures taken from PubChem Public Chemical Database www.ncbi.nlm.nih.gov/pccompound).

Figure 1.

Summary of the molecular structures and various names of vitamin D and its related compounds (molecular structures taken from PubChem Public Chemical Database www.ncbi.nlm.nih.gov/pccompound).

It was assumed that exposure of the skin to UV radiation drove the conversion of 7-dehydrocholesterol to cholecalciferol (step 1, Fig. 2). However, proof of this emerged more than 30 yr later with independent discoveries by two groups: Holick et al. (39) and Esvelt et al. (40). The photo-production is subject to a variety of factors including amount of UV exposure (latitude, season, and use of sunscreen and clothing), ethnicity (skin pigmentation), and age (41–43). After the photochemical conversion of 7-dehydrocholesterol to pre-vitamin D₃ and its thermal isomerization to vitamin D₃, it binds to the vitamin D-binding protein (DBP), and is transported to the liver where a hydroxyl group is attached at the carbon-25 atom (i.e. C-25) to generate 25-hydroxyvitamin D (25D) (step 2, Fig. 2). The importance of the liver in this first phase of hydroxylation was reported in 1969 by DeLuca and colleagues (44). A number of 25-hydroxylases have been reported including cytochrome P450 CYP27A1 and CYP2R1 (45, 46). CYP2R1 is probably the major enzyme required for 25-hydroxylation of vitamin D₃, at least in humans (47, 48). A patient with classic rickets and low circulating levels of 25D was found to have a homozygous mutation of the CYP2R1 gene, implying that other enzymes were unable to compensate (49).

Much remains unknown about the 25-hydroxylase enzymes including the significance of their reported presence in skin, kidney, and intestine (50). These enzymes are generally considered to be constitutively expressed with little feedback regulation; however, this is unusual for the CYP family (50). In the absence of severe hepatic dysfunction, 25-hydroxylation of vitamin D is not usually rate limiting. However, in mild to moderate liver impairment, the associated fat malabsorption can cause vitamin D deficiency.

In contrast, 1α-hydroxylation is the major rate-limiting step in synthesis of 1,25-dihydroxyvitamin D (1,25D) (step 3, Fig. 2). Synthesis of 1,25D is tightly regulated (51) and is mediated by the enzyme 1α-hydroxylase. Factors regulating 1α-hydroxylase in kidney are shown in Fig. 2. Due to its sequence similarity to CYP27A1, the gene encoding 1α-hydroxylase was called CYP27B1 (52). Its role was demonstrated in 1998 by the development of rickets and reduced circulating 1,25D levels in four patients with gene mutations for this enzyme (53). Cyp27B1-null mice also develop rickets with reduced levels of circulating 1,25D (54).

CYP27B1 mRNA is expressed in a number of vitamin D target tissues including kidney, skin, intestine, macrophages, and bone. Although its expression is relatively high in skin, the kidney is thought to be primarily responsible for circulating levels of 1,25D (50). This is supported by 1,25D deficiency in people with renal failure (55, 56). However, this has not been conclusively proven with renal-specific CYP27B1 deletion. The presence of CYP27B1 in other cell types, especially macrophages, is demonstrated by the fact that people with granulomatous diseases can have elevated 1,25D levels (57).

Entry of 25D into the proximal renal tubular cells requires receptor-mediated uptake of DBP plus 25D at the brush border, degradation of DBP by legumain, and endocytic internalization and translocation of 25D to mitochondria (58). Megalin, a member of the low-density lipoprotein receptor family, is required for reabsorption of filtered DBP-bound 25D (59). It is in the mitochondria that 1α-hydroxylation of 25D into its biologically active form, 1,25D, occurs (50). A number of factors contribute to the tight regulation of 1α-hydroxylase enzyme expression and activity in the kidney (Fig. 2). These include calcium, PTH, calcitonin, GH, IGF-I, and fibroblast growth factor 23 (FGF23). In addition, 1,25D negatively regulates its own synthesis by suppressing 1α-hydroxylase expression in kidney and bone (60). There is also evidence to suggest that estrogen, progesterone, and prolactin may regulate 1α-hydroxylase activity (61, 62). In macrophages, regulation of CYP27B1 is primarily cytokine mediated (63).

The final important enzyme in the vitamin D endocrine system is 24-hydroxylase (CYP24A1). Found in nearly all cells and highly expressed by the kidney, CYP24A1 limits the amount of 1,25D in target tissues by converting 1,25D to inactive metabolites, including 1,24,25-(OH)₃D and calcitroic acid and by converting 25D to 24,25(OH)₂D (step 4, Fig. 2). In addition to 24-hydroxylation, this multicatalytic enzyme is able to catalyze side-chain hydroxylations at the C23 and C26 positions (64). Recently, mutations in CYP24A1 were reported in six children with infantile hypercalcemia, thereby providing conclusive evidence of the importance of this enzyme in the in vivo regulation of vitamin D metabolism (65).

The VDR, to which 1,25D binds to exert its biological effects, was described in 1974 by Brumbaugh and Haussler (66). This is depicted in Fig. 3. Insights into the structure and function of this protein have been gained via the cloning and subsequent analysis of the recombinant protein (67), by x-ray crystallography (68) and molecular modeling using atomic coordinates of the protein x-ray structure (69). The protein comprises three distinct regions: an N-terminal dual zinc finger domain that binds to DNA (a characteristic feature of the steroid receptor family), a C-terminal domain that binds to 1,25D, and an extensive, unstructured region that links these two functional domains.

Figure 3.

Classic vitamin D signaling pathway. Vitamin D binds to its receptor, which dimerizes, preferentially with RXR. This complex binds to VDRE in the DNA to regulate transcription.

Figure 3.

Classic vitamin D signaling pathway. Vitamin D binds to its receptor, which dimerizes, preferentially with RXR. This complex binds to VDRE in the DNA to regulate transcription.

Binding of 1,25D to VDR leads to conformational changes within the receptor that allows it to interact with its heterodimeric partner, retinoid X receptor (RXR) (Fig. 3) (70). VDR also forms homodimers that bind DNA and regulate gene expression (71). The liganded complex (i.e. 1,25D-VDR-RXR) binds to vitamin D response elements (VDRE) in the DNA (72). Classic VDRE are direct repeats of two hexameric core binding sites with a three-nucleotide separation (73, 74). However, numerous nonclassic sites have been proven to act as VDRE.

VDR-containing dimers interact with large coregulatory complexes required for gene modulation (70, 75). Although a number of coregulatory molecules have been characterized including the VDR interacting protein and the steroid receptor coactivator complex (SRC), the precise mechanisms by which these molecules operate are just beginning to emerge (76). The system is more complex, because VDR is one of the few nuclear hormone receptors that has been clearly demonstrated to be able to regulate gene expression in the absence of ligand. Unliganded VDR dimers can bind to and regulate some genes, mostly to repress their expression. This is thought to be the mechanism for spontaneous hair loss in mice with mutations in VDR (77). Expression of the VDR in virtually every tissue and the diverse phenotypic changes in the VDRKO mouse are consistent with the wide spectrum of activity of the 1,25D-VDR endocrine system (13).

As well as regulation of VDR, CYP27B1, and CYP24A1 (78, 79), the 1,25D-VDR-RXR complex is involved in regulation of a variety of cellular functions including DNA repair, cell differentiation, apoptosis, metabolism, and oxidative stress (13). Its effects on calcium and mineral homeostasis are well established and, in brief, result from the transcriptional regulation of specific proteins within the intestine (calcium-binding proteins, calbindin D28k, and epithelial calcium channels), bone (osteocalcin, osteopontin, and receptor activator of nuclear factor-κB ligand), and parathyroid glands (PTH) (80). These effects provide potential indirect routes for regulation of muscle function in addition to direct effects (Fig. 4).

Figure 4.

Direct and indirect effects of vitamin D on muscle. Data on direct effects come predominantly from in vitro studies and are yet to be confirmed in vivo, where the presence of the VDR is currently under debate.

Figure 4.

Direct and indirect effects of vitamin D on muscle. Data on direct effects come predominantly from in vitro studies and are yet to be confirmed in vivo, where the presence of the VDR is currently under debate.

This review will focus on diverse effects of the vitamin D endocrine system on the functional and metabolic capacity of skeletal muscle as reported by a range of clinical and translational studies. We will also discuss the central role of skeletal muscle in our emerging understanding of the nongenomic capabilities of the VDR.

B. Skeletal muscle physiology

Skeletal muscle is estimated to account for 42% of total body mass in males and 35% in females (81). Its primary function is to generate force and to provide locomotion. The functional units of skeletal muscle are the muscle fibers, themselves comprised of many myofibrils. Myofibrils are long cylindrical multinucleated cells that vary considerably in their morphological, biochemical, and physiological properties, thereby forming the basis of the well-known structural and functional diversity of skeletal muscle (82). This complexity causes difficulty in classifying muscle fibers. At one stage, one author described fiber classification as "showing an alarming trend toward the incomprehensible" (83).

At this time, the most widely used classification is based on histochemical methods that determine the pH lability of myofibrillar ATPase activity and divides fibers into type I (low activity) and type II (high activity) with further subdivision into IIA, IIX, and IIB (84) depending on the expression of different myosin heavy chain (MHC) forms (summarized in Table 1). The reliance on oxidative or glycolytic metabolic pathways determines the contractile speed of these various fiber types. There is substantial evidence that muscle fibers are dynamic in their response to a variety of contractile and metabolic stimuli and are able to convert from one fiber type to another or undergo atrophy (84). Both vitamin D deficiency and age-related sarcopenia have been associated with preferential atrophy of type II (fast-twitch) fibers (84, 85).

Table 1.

Respective characteristics of muscle fiber types based on the current classification

	Type I	Type IIA	Type IIX	Type IIB
mATPase activity	Low	High	High	High
MHC type	I-MHC	IIa-MHC	IIx-MHC (rodents), IIb-MHC (humans)	IIb-MHC
Mitochondrial density	High	High	Medium	Low
Anatomic color	Red	Red	White	White
Energy source	Oxidative	Mainly oxidative	Oxidative and glycolytic	Mainly glycolytic
Activity	Aerobic	Anaerobic (long-term)	Aerobic (short-term)	Aerobic (short-term)
Contractile speed	Slow	Moderately fast	Fast	Very Fast
Resistance to fatigue	High	High	Moderate	Low

	Type I	Type IIA	Type IIX	Type IIB
mATPase activity	Low	High	High	High
MHC type	I-MHC	IIa-MHC	IIx-MHC (rodents), IIb-MHC (humans)	IIb-MHC
Mitochondrial density	High	High	Medium	Low
Anatomic color	Red	Red	White	White
Energy source	Oxidative	Mainly oxidative	Oxidative and glycolytic	Mainly glycolytic
Activity	Aerobic	Anaerobic (long-term)	Aerobic (short-term)	Aerobic (short-term)
Contractile speed	Slow	Moderately fast	Fast	Very Fast
Resistance to fatigue	High	High	Moderate	Low

References are Schiffiano (353), Spagenburg and Booth (354), Berchtold et al. (82), and Brooke and Kaiser (83). mATPase, Myofibrillar ATPase.

Table 1.

Respective characteristics of muscle fiber types based on the current classification

	Type I	Type IIA	Type IIX	Type IIB
mATPase activity	Low	High	High	High
MHC type	I-MHC	IIa-MHC	IIx-MHC (rodents), IIb-MHC (humans)	IIb-MHC
Mitochondrial density	High	High	Medium	Low
Anatomic color	Red	Red	White	White
Energy source	Oxidative	Mainly oxidative	Oxidative and glycolytic	Mainly glycolytic
Activity	Aerobic	Anaerobic (long-term)	Aerobic (short-term)	Aerobic (short-term)
Contractile speed	Slow	Moderately fast	Fast	Very Fast
Resistance to fatigue	High	High	Moderate	Low

	Type I	Type IIA	Type IIX	Type IIB
mATPase activity	Low	High	High	High
MHC type	I-MHC	IIa-MHC	IIx-MHC (rodents), IIb-MHC (humans)	IIb-MHC
Mitochondrial density	High	High	Medium	Low
Anatomic color	Red	Red	White	White
Energy source	Oxidative	Mainly oxidative	Oxidative and glycolytic	Mainly glycolytic
Activity	Aerobic	Anaerobic (long-term)	Aerobic (short-term)	Aerobic (short-term)
Contractile speed	Slow	Moderately fast	Fast	Very Fast
Resistance to fatigue	High	High	Moderate	Low

References are Schiffiano (353), Spagenburg and Booth (354), Berchtold et al. (82), and Brooke and Kaiser (83). mATPase, Myofibrillar ATPase.

On a macroscopic scale, the generation of force by a muscle is dependent on several factors including size, fiber composition, and individual fiber functional capacity. The cross-sectional area is the sum of the individual, parallel fibers, themselves made up of thousands of individual myofibrils and other cell types (86). The sarcomere is the basic unit of contraction and is defined as the portion of the myofibril that lies between two bands, known as Z bands. Between successive Z bands, an array of myosin and actin molecules are intricately arranged to form alternating filaments, suspended in the sarcoplasm and lying in close proximity to mitochondria, indicative of the significance of ATP in contraction. The role of calcium, also fundamentally important in the tight regulation of muscle contraction (87), will be discussed below.

Apart from the generation of force, skeletal muscle is a highly metabolic tissue that produces and responds to a variety of hormones and factors, leading one author to describe it as a true endocrine organ (88). Exercise leads to the increased expression and secretion of a family of myokines including IL-6 and brain-derived neurotrophic factor that can stimulate glucose uptake and fat oxidation within muscle, lipolysis in adipocytes, and gluconeogenesis in hepatocytes via various autocrine, paracrine, and endocrine pathways (87, 89). Skeletal muscle is also responsive to a range of hormones including, but not limited to, insulin, IGF, glucocorticoids, thyroid hormones, and 1,25D, all of which exert influences on the differentiation, metabolism, and function of muscle via a number of established and evolving mechanisms.

C. Calcium and muscle contraction

As well as regulating whole-body calcium homeostasis, there is also evidence that 1,25D increases calcium influx in muscle cells and thus may have both direct and indirect calcium-related effects on muscle (Fig. 4) (90). The sliding filament theory, first proposed in 1954 (91), describes the highly complex movement of actin and myosin filaments over each other. This and potential effects by which vitamin D may affect this model, based on data to be discussed, are depicted in Fig. 5. It is primarily the influx of calcium from the sarcoplasmic reticulum (SR) and binding to the troponin-tropomyosin complex that results in the exposure of active binding sites on the actin filament and their engagement with the myosin heads (82). In the presence of ATP, contraction ensues as the myosin head tilts from an obtuse angle to the perpendicular, causing movement of myosin over actin filaments in a process named the power stroke, after which ADP and inorganic phosphate are released (86). The binding of new ATP to the myosin head causes its detachment from the active site of the actin filament and movement back into the obtuse position.

Figure 5.

Potential roles of vitamin D in the sliding-filament model of muscle contraction. These potential effects, marked with an asterisk, include the rapid flux of calcium ions from the SR to cytoplasm (319), the expression of actin and troponin-tropomyosin proteins (152, 153), and the effects of vitamin D-mediated phosphate homeostasis on ATP (326).

Figure 5.

Potential roles of vitamin D in the sliding-filament model of muscle contraction. These potential effects, marked with an asterisk, include the rapid flux of calcium ions from the SR to cytoplasm (319), the expression of actin and troponin-tropomyosin proteins (152, 153), and the effects of vitamin D-mediated phosphate homeostasis on ATP (326).

D. Calcium and exercise-related glucose uptake

Calcium plays a vital role in exercise-related glucose uptake by skeletal muscle. Vitamin D regulates calcium homeostasis, giving potential for indirect regulation. Exercise increases glucose transporter 4 (GLUT4) expression; after contraction, increased cytosolic calcium activates Ca²⁺/calmodulin-dependent protein kinase (CAMK) pathways and causes transcriptional up-regulation of myocyte enhancer factors 2A and 2D, which increase GLUT4 expression (92–94). Exercise also increases GLUT4 translocation to the muscle cell membrane, independently of insulin. Activation of the AMP-kinase pathway contributes to this process (95). GLUT4 vesicle translocation and insertion into the cell membrane is a calcium- and ATP-dependent process (96). A putative mechanism for this is the synaptotagmins. They are calcium-sensitive proteins required for insertion of the GLUT4 proteins into the cell membrane, as demonstrated in adipocytes (97). Synaptotagmins in turn regulate Myo1c, an actin-filament-attached protein that binds to and transports GLUT4 vesicles (98). Contraction-induced calcium influx stimulates a range of signaling pathways that regulate muscle differentiation and function (99, 100). These include myogenic transcription factors, myostatin, peroxisome proliferator-activated receptor δ and utrophin A, mainly via CAMK and calcineurin-mediated pathways (82, 99, 101). These processes, generally referred to as excitation-transcription coupling, give rise to the plasticity and unique adaptive ability of muscle to alter vital components in its function, fiber type, and contractile force on demand.

E. Calcium and insulin-stimulated glucose uptake

Skeletal muscle is responsible for approximately 85% of insulin-mediated glucose uptake in lean individuals (102). Insulin induces translocation of GLUT4 to the cell surface, facilitating glucose uptake and clearance of circulating glucose. Insulin binds to the α-subunits of its receptor, activating a signaling cascade. This has been covered in many elegant reviews (103, 104). The mechanisms by which the activation of these proteins then leads to the insertion of GLUT4 protein into the cell membrane remain incompletely understood but have also been the subject of recent review (105). As with exercise, GLUT4 vesicle translocation is ATP and calcium dependent.

Pharmacological inhibition of calcium influx in muscle reduces insulin-mediated glucose uptake, independent of effects on Akt (96). Calcium regulates components of the proximal insulin signaling pathway such as the binding of calmodulin to insulin receptor substrate (IRS)-2 (106). Increases in calcium influx improved insulin-mediated glucose uptake in isolated muscle fibers of both normal and insulin-resistant mice (96). Calcium regulates cytoskeletal components involved in GLUT4 translocation (98). Studies on L6 myotubes reported significant increases in GLUT4 expression in response to caffeine-related increases in intracellular calcium. The effects were negated by dantrolene, an inhibitor of SR calcium release (92). However, additional research examining the role of calcium in insulin sensitivity is needed.

III. Vitamin D and Muscle: Cell Models

On a cellular level, a variety of mechanisms by which vitamin D impacts upon the function of skeletal muscle have been elucidated. These can be broadly divided into 1) genomic effects that arise from the binding of the 1,25D-VDR-RXR heterodimer at specific nuclear receptors to influence gene transcription and 2) nongenomic effects that arise from a host of complex intracellular signal transduction pathways after binding of 1,25D to nonnuclear receptor. Over the past 30 yr, the majority of research in this area has mainly focused on the nongenomic effects of vitamin D on skeletal muscle, in particular its regulation of protein kinase A (PKA)/cAMP, protein kinase B, protein kinase C (PKC), CAMK, and multiple MAPK pathways (90).

A. VDR in muscle

After the discovery of the VDR in 1969 (107), the isolation of unoccupied 1,25D receptors partitioned between the cytosol and cell nucleus in intestinal cells in 1980 raised the possibility of rapid, nontranscriptional pathways associated with this receptor (108). The rapidity, over minutes, with which 1,25D treatment resulted in changes in intracellular calcium transport in vascularized duodenal cells supported this possibility (109). Furthermore, it became apparent from studies that examined the binding properties of VDR isolated from the caveolae-enriched membrane fraction of chick intestinal cells that the cytosolic receptors were identical to nuclear VDR (110). To confirm this, significant reductions in the capacity of [³H]1,25D to bind to isolated caveolae-membrane fractions were reported in tissues obtained from VDRKO mice (110). Studies examining the Tokyo strain of VDRKO mice, in which the second zinc finger of the DNA-binding domain of VDR is ablated, reported some residual binding of 1,25D in kidney cells (111).

Treatment with 1,25D elicits rapid uptake of calcium within muscle cells in vitro and in vivo (112). However, after transfection of muscle cells with anti-VDR antisense oligodeoxynucleotides (ODN), 1,25D-dependent mechanisms by which rapid calcium entry occurs, namely store-operated calcium entry (SOCE) or capacitative calcium entry, are inhibited (113, 114), therefore implying a direct nongenomic role for VDR in calcium handling.

The presence of the VDR has been reported in avian, murine, and human muscle cells on the basis of immunohistochemistry (20, 115), equilibrium binding studies (25), and detection of VDR mRNA by RT-PCR (21). However, these findings are subject to challenge due to the nonspecificity of many of the VDR antibodies (116). A recent paper that used a validated antibody (which did not show bands in VDRKO mice) did not find VDR expression in skeletal, cardiac, or smooth muscle by Western blot and immunohistochemistry (27). Differences in experimental conditions and the possibility of tight protein binding of VDR to DNA may have accounted for this finding. Moreover, low levels may be sufficient for significant function in muscle. Major studies examining the presence of VDR in muscle and the various techniques used have been summarized in Table 2.

Table 2.

Major studies examining the presence of VDR in muscle (listed in chronological order)

Study	Muscle cell type	Method of detection	Findings in muscle
Neville and DeLuca, 1966 (355)	Rat muscle extracts	Tritium-labeled 1,25D	Proportion of 1,25D localized to membrane
Stumpf et al. 1979 (356)	Rat muscle extracts	Tritium-labeled 1,25D, autoradiography	1,25D not localized in muscle
Simpson et al. 1985 (25)	Cultured G8 and H9c2 myoblasts; rat longissimus muscle	Equilibrium binding studies, chromatography	VDR present
Costa et al. 1986 (26)	Cloned human muscle cells (five individuals)	Binding studies, chromatography, 24-hydroxylase assay	VDR present
Boland et al. 1985 (357)	Chick myoblast cells	Density gradient analysis, saturation analysis	VDR present
Sandgren et al. 1991 (358)	Rat muscle extracts	Immunoradiometric assay	VDR absent
Buitrago et al. 2000, 2001 (119, 120)	Chick skeletal muscle cells	Western blot	VDR present
Boland et al. 2002 (145)	Chick skeletal muscle cells	Western blot	VDR present
Buitrago and Boland 2010 (20)	C2C12 cell line	Immunohistochemistry	VDR present
Endo et al. 2003 (21)	Mouse muscle extracts	RT-PCR	VDR mRNA present in muscle of 3-wk-old mice but not 8-wk-old mice
Bischoff et al. 2001 (115)	Human muscle extracts (20 people)	Immunohistochemistry (VDR-9A7 antibody)	VDR present and decreases with age
Garcia et al. 2011 (118)	C2C12 cell line	RT-PCR, immunohistochemistry, Western blot (VDR-C20 antibody)	VDR present
Wang and DeLuca 2011 (27)	Mouse and human muscle extracts	RT-PCR, immunohistochemistry, Western blot (VDR-D6 antibody)	VDR mRNA at a low level; protein for VDR not detected (using D6 antibody); C20 antibody not specific

Study	Muscle cell type	Method of detection	Findings in muscle
Neville and DeLuca, 1966 (355)	Rat muscle extracts	Tritium-labeled 1,25D	Proportion of 1,25D localized to membrane
Stumpf et al. 1979 (356)	Rat muscle extracts	Tritium-labeled 1,25D, autoradiography	1,25D not localized in muscle
Simpson et al. 1985 (25)	Cultured G8 and H9c2 myoblasts; rat longissimus muscle	Equilibrium binding studies, chromatography	VDR present
Costa et al. 1986 (26)	Cloned human muscle cells (five individuals)	Binding studies, chromatography, 24-hydroxylase assay	VDR present
Boland et al. 1985 (357)	Chick myoblast cells	Density gradient analysis, saturation analysis	VDR present
Sandgren et al. 1991 (358)	Rat muscle extracts	Immunoradiometric assay	VDR absent
Buitrago et al. 2000, 2001 (119, 120)	Chick skeletal muscle cells	Western blot	VDR present
Boland et al. 2002 (145)	Chick skeletal muscle cells	Western blot	VDR present
Buitrago and Boland 2010 (20)	C2C12 cell line	Immunohistochemistry	VDR present
Endo et al. 2003 (21)	Mouse muscle extracts	RT-PCR	VDR mRNA present in muscle of 3-wk-old mice but not 8-wk-old mice
Bischoff et al. 2001 (115)	Human muscle extracts (20 people)	Immunohistochemistry (VDR-9A7 antibody)	VDR present and decreases with age
Garcia et al. 2011 (118)	C2C12 cell line	RT-PCR, immunohistochemistry, Western blot (VDR-C20 antibody)	VDR present
Wang and DeLuca 2011 (27)	Mouse and human muscle extracts	RT-PCR, immunohistochemistry, Western blot (VDR-D6 antibody)	VDR mRNA at a low level; protein for VDR not detected (using D6 antibody); C20 antibody not specific

Table 2.

Major studies examining the presence of VDR in muscle (listed in chronological order)

Study	Muscle cell type	Method of detection	Findings in muscle
Neville and DeLuca, 1966 (355)	Rat muscle extracts	Tritium-labeled 1,25D	Proportion of 1,25D localized to membrane
Stumpf et al. 1979 (356)	Rat muscle extracts	Tritium-labeled 1,25D, autoradiography	1,25D not localized in muscle
Simpson et al. 1985 (25)	Cultured G8 and H9c2 myoblasts; rat longissimus muscle	Equilibrium binding studies, chromatography	VDR present
Costa et al. 1986 (26)	Cloned human muscle cells (five individuals)	Binding studies, chromatography, 24-hydroxylase assay	VDR present
Boland et al. 1985 (357)	Chick myoblast cells	Density gradient analysis, saturation analysis	VDR present
Sandgren et al. 1991 (358)	Rat muscle extracts	Immunoradiometric assay	VDR absent
Buitrago et al. 2000, 2001 (119, 120)	Chick skeletal muscle cells	Western blot	VDR present
Boland et al. 2002 (145)	Chick skeletal muscle cells	Western blot	VDR present
Buitrago and Boland 2010 (20)	C2C12 cell line	Immunohistochemistry	VDR present
Endo et al. 2003 (21)	Mouse muscle extracts	RT-PCR	VDR mRNA present in muscle of 3-wk-old mice but not 8-wk-old mice
Bischoff et al. 2001 (115)	Human muscle extracts (20 people)	Immunohistochemistry (VDR-9A7 antibody)	VDR present and decreases with age
Garcia et al. 2011 (118)	C2C12 cell line	RT-PCR, immunohistochemistry, Western blot (VDR-C20 antibody)	VDR present
Wang and DeLuca 2011 (27)	Mouse and human muscle extracts	RT-PCR, immunohistochemistry, Western blot (VDR-D6 antibody)	VDR mRNA at a low level; protein for VDR not detected (using D6 antibody); C20 antibody not specific

Study	Muscle cell type	Method of detection	Findings in muscle
Neville and DeLuca, 1966 (355)	Rat muscle extracts	Tritium-labeled 1,25D	Proportion of 1,25D localized to membrane
Stumpf et al. 1979 (356)	Rat muscle extracts	Tritium-labeled 1,25D, autoradiography	1,25D not localized in muscle
Simpson et al. 1985 (25)	Cultured G8 and H9c2 myoblasts; rat longissimus muscle	Equilibrium binding studies, chromatography	VDR present
Costa et al. 1986 (26)	Cloned human muscle cells (five individuals)	Binding studies, chromatography, 24-hydroxylase assay	VDR present
Boland et al. 1985 (357)	Chick myoblast cells	Density gradient analysis, saturation analysis	VDR present
Sandgren et al. 1991 (358)	Rat muscle extracts	Immunoradiometric assay	VDR absent
Buitrago et al. 2000, 2001 (119, 120)	Chick skeletal muscle cells	Western blot	VDR present
Boland et al. 2002 (145)	Chick skeletal muscle cells	Western blot	VDR present
Buitrago and Boland 2010 (20)	C2C12 cell line	Immunohistochemistry	VDR present
Endo et al. 2003 (21)	Mouse muscle extracts	RT-PCR	VDR mRNA present in muscle of 3-wk-old mice but not 8-wk-old mice
Bischoff et al. 2001 (115)	Human muscle extracts (20 people)	Immunohistochemistry (VDR-9A7 antibody)	VDR present and decreases with age
Garcia et al. 2011 (118)	C2C12 cell line	RT-PCR, immunohistochemistry, Western blot (VDR-C20 antibody)	VDR present
Wang and DeLuca 2011 (27)	Mouse and human muscle extracts	RT-PCR, immunohistochemistry, Western blot (VDR-D6 antibody)	VDR mRNA at a low level; protein for VDR not detected (using D6 antibody); C20 antibody not specific

Another possibility is that there may be differences in the expression of VDR in muscle in different species and throughout the various stages of muscle differentiation. In support of the latter, in vitro studies predominantly examine the activity of VDR within myoblasts and myotubes rather than fully differentiated adult cells. In vivo, VDR mRNA was reported in the muscle of 3-wk-old wild-type mice but not in their 8-wk-old counterparts (21). The authors suggested a primary role for VDR in early muscle development (21). Thus, the expression of VDR within muscle over time requires further clarification.

Within cultured chick myoblasts, VDR translocates from the nucleus to the cytoplasm quite rapidly (i.e. 1–10 min) after exposure to 1,25D (117). Intact microtubular transport and caveolae structure were essential as demonstrated by the disruption of VDR translocation by inhibition of these individual components in C2C12 cells (i.e. with colchicine and methyl-β-cyclodextrin, respectively) (20). After a longer period of exposure to 1,25D, the VDR appears to translocate back to the nucleus to presumably carry out its role in transcriptional regulation. This shuttling of the VDR between cytoplasm and nucleus indicates its versatility in both rapid and genomic actions, depending on location (118).

Coimmunoprecipitation analyses have also demonstrated direct binding of the VDR with a component of the tyrosine phosphorylation cascade, namely c-Src, under the influence of 1,25D (119). Transfection of muscle cells with three different anti-VDR antisense ODN inhibited 1,25D-dependent dephosphorylation and subsequent activation of c-Src as assessed 15 min after treatment with 1,25D or vehicle (120). More recently, treatment of muscle cells with 1,25D resulted in VDR binding with c-Src, time-dependent increases in c-Src activity, and the redistribution of c-Src from the periplasma membrane zone, where it resides under basal conditions, to the cytoplasm and nucleus as seen on confocal microscopy (20). There is also evidence that 1,25D induces the association between c-Src and c-myc, a transcription factor involved in cell growth and apoptosis. This evidence includes coimmunoprecipitation analyses that demonstrate 1,25D-mediated formation of complexes between c-Src and c-myc (20) and significant inhibition (i.e. 94%) of 1,25D-mediated c-myc tyrosine phosphorylation on immunoblot after transfection of muscle cells with anti-VDR antisense ODN (120) or treatment with PP1, a c-Src-specific inhibitor (120). Mechanistically, c-Src probably interacts with VDR and c-myc, both of which are hormone-dependent phosphotyrosine proteins, via its Src homology 2 domain, but this requires further evaluation (121). A role for caveolin-1 in 1,25D-mediated activation of c-Src has also been suggested. Caveolin-1 belongs to a family of membrane-scaffolding proteins with potential roles in different disease phenotypes and binds to c-Src under basal conditions near the cell membrane. After treatment of C2C12 myoblasts with 1,25D, colocalization of caveolin-1 and c-Src was disturbed, and they were redistributed into cytoplasm and nucleus (20). Interestingly, when the caveolae structure was disrupted by methyl-β-cyclodextrin, 1,25D was not able to separate caveolin-1 from c-Src, preventing its activation and also preventing the nuclear translocation of VDR. Therefore, the caveolae and associated proteins appear to play an upstream role in the activation of c-Src. It also appears that 1,25D-mediated activation of c-Src by VDR is a downstream regulator of several nongenomic effects of 1,25D in muscle, specifically involving differentiation and calcium homeostasis, which we will discuss.

Apart from the specific ability of the VDR to translocate from nucleus to cytosol in response to 1,25D, conformational changes within the highly flexible 1,25D molecule also determine the mediation of genomic and nongenomic actions via its receptor. It has been shown that the relatively planar 6-s-cis locked JN [1,25-(OH)₂-lumisterol₃] displays nongenomic activity and that the 6-s-trans locked JB [1,25-(OH)₂-dihydrotachysterol₃] possesses predominantly genomic activity on binding the VDR (69). By molecular modeling of the VDR using atomic coordinates of the protein x-ray structure and computer docking, specific binding sites on the VDR that determine its functional activity have been reported (122, 123). Interestingly, the pockets that, respectively, mediate the regulation of nongenomic and genomic responses overlap and therefore result in mutually exclusive conformational forms of the VDR. It has been suggested that the unbound VDR may possibly exist in the cytoplasm as multiple, equilibrating receptor conformations according to standard statistical distribution (69). Also intriguing, a potential role for 25D in binding the alternative pocket and initiating intracellular calcium flux has recently been reported (123).

Apart from the VDR, it is also possible that other cytosol receptors may be responsible for the rapid actions of 1,25D in muscle. Contrary to an earlier report, it does not appear that annexin II binds to 1,25D in a physiologically relevant manner (124, 125). Recent data have suggested a role for membrane-associated rapid response steroid binding in potentially inducing rapid effects of 1,25D in muscle, but further assessment is required (126).

B. Calcium homeostasis

Although the nongenomic regulation of intracellular calcium by 1,25D has been well characterized in cultured myoblasts and myotubes, it has also been confirmed by in vivo studies on chicks and in vitro assessment of differentiated soleus muscle samples. Studies report a time- and dose-dependent increase in intracellular muscle calcium uptake in response to 1,25D. The use of particular agents and antisense oligonucleotides to block components of the signal transduction pathway has led to the elucidation of specific step-wise mechanisms by which vitamin D influences intracellular calcium homeostasis (127–129). These have been depicted in Fig. 6.

Figure 6.

Mechanisms by which vitamin D influences calcium homeostasis in cultured muscle cells. c-Src, cellular Src; PI3-kinase, phosphoinositide 3-kinase; PKA, protein kinase A; PLC-γ, phospholipase Cγ.

Figure 6.

Mechanisms by which vitamin D influences calcium homeostasis in cultured muscle cells. c-Src, cellular Src; PI3-kinase, phosphoinositide 3-kinase; PKA, protein kinase A; PLC-γ, phospholipase Cγ.

First, the rapid mobilization of calcium from the SR into the cytosol relies on 1,25D-dependent activation of two components of the signal transduction pathway, namely c-Src and phosphoinositide-3 kinase. These in turn lead to the activation of phospholipase Cγ, the rapid production of inositol triphosphate (IP3) and the first of two phases of diacylglycerol (DAG) synthesis from the membrane phosphoinositides (22, 130). It is IP3 that then mediates the rapid movement of calcium from the SR into the cytosol (130).

In the continued presence of 1,25D, two additional processes are then involved in the more sustained phase of calcium entry from the extracellular compartment, namely SOCE and L-type voltage-dependent calcium-channel (VDCC) entry mechanisms. SOCE relies on several factors including IP3-dependent calcium release from the SR that activates calmodulin, CAMKII, and PKC, the latter also being activated by a by-product of a previous reaction, namely DAG (131). The particular channels responsible for SOCE have been identified as the transient receptor potential-canonical-like proteins. Interestingly, a direct role of the VDR in activating these channels has been suggested by the coimmunoprecipitation of both molecules after treatment with 1,25D in chick skeletal muscle cells (113).

Apart from its reported role in SOCE, evidence supports vital additional roles for PKC in 1,25D-dependent calcium homeostasis in muscle. Rapid translocation of PKC-α from the cytosol to the cell membrane after the in vitro treatment of chick soleus muscle and cultured rat and chick myoblasts with 1,25D (132, 133) and marked reduction in intracellular calcium influx after selective knockout of PKC-α by the use of specific antisense oligonucleotides have been described (128). Furthermore, PKC also activates VDCC-mediated calcium entry as evidenced by the rapid stimulation of ⁴⁵Ca²⁺ uptake by cultured myoblasts after treatment with PKC activators, namely DAG and phorbol 12-myristate 13-acetate, inhibited by the addition of nifedipine, an L-type VDCC blocker (133). PKC-α may also have a role in the 1,25D-dependent activation of the ERK1/2 signaling pathway as will be discussed in Section III.D on proliferation and differentiation.

VDCC-mediated calcium entry also relies on 1,25D-dependent activation of the cAMP/PKA pathway. Very rapid increases (within 30 sec) in the levels of adenylyl cyclase (AC) and cAMP levels, together with increased PKA activity, occur in differentiated muscle cells and cultured myotubes after 1,25D treatment (127, 134). These studies also report that 1,25D stimulation of VDCC-⁴⁵Ca²⁺ entry can be mimicked by treatment with dibutyryl cAMP and abolished by specific inhibitors of AC and PKA.

Another mechanism is emerging by which PKC and cAMP/PKA pathways may cross talk in the regulation of VDCC-mediated calcium flux (90). The preliminary data indicates an increase in the cAMP content of myoblasts after treatment with a PKC activator, phorbol 12-myristate 13-acetate, which may stem from the phosphorylation of Gαi that is mediated by PKC in other cells (133). Furthermore, the phosphorylation of Gαi in myoblast membranes after treatment with 1,25D is likely to be essential in the stimulation of AC activity as evidenced by the effects of abolishing G protein regulatory pathways on 1,25D-mediated AC activity (134).

In summary, 1,25D induces changes in intracellular calcium levels in cultured muscle cells initially via rapid IP3-dependent calcium shifts from the SR to the cytosol followed by processes resulting in extracellular calcium influx via the activation of SOCE and VDCC activity. These mechanisms are evident in both immature myoblasts and differentiated myotubes, suggesting a potential role for rapid calcium influx in muscle cell differentiation and contraction, respectively (19). In support of this inference, an interesting report from 1974 described a direct correlation between in vivo skeletal muscle dysfunction and demonstrable defects in intracellular calcium handling (136). A group of rabbits, rendered vitamin D deficient by dietary methods, were found to be substantially weaker and hypotonic compared with their vitamin D- replete counterparts and in vitro, displayed significant reductions in calcium uptake in the SR on isolation from psoas muscle.

C. Phosphate homeostasis

Phosphate is an essential substrate in the production of ATP and in protein synthesis. There is early evidence demonstrating that phosphate uptake in muscle may be influenced by 25D (19, 137). The administration of 25D to vitamin D-deficient, phosphate-deplete rats resulted in a significant increase in the in vitro concentration of [³²P]phosphate in muscle cells, followed by the stimulation of phosphate-dependent metabolic processes including ATP synthesis in these cells (137). This effect was not reproduced by the repletion of phosphate in these rats. The abolition of 1α-hydroxylase activity by nephrectomy had no effect on 25D-mediated phosphate uptake, implying a direct role of the prehormone in this process. Another study reported the specificity of 25D on in vitro phosphate uptake of differentiated muscle cells with the absence of such effects after 1,25D and 24,25-(OH)₂D treatment (138–140).

Another study demonstrated the specific transport of [³²P]phosphate across muscle plasma membranes after in vivo vitamin D repletion and ³²P labeling of vitamin D-deficient chicks (141). This finding was later confirmed by an increase in vesicle phosphate transport in muscle cells via the isolation of highly purified sarcolemma vesicles in vitamin D-deficient chicks treated with vitamin D (19). The direct effect on phosphate uptake may be mediated via a sodium-dependent mechanism as reported by studies on cultured muscle cells (138, 139).

D. Proliferation and differentiation

There is evidence that 1,25D activates components of the MAPK family in cultured myoblasts, thereby influencing the expression of genes involved in cellular proliferation and differentiation. The majority of research in this area has focused on the effects of 1,25D on the ERK1/2 signaling pathway. The initial activation of c-Src by 1,25D, previously described as an apparent gateway to the nongenomic effects of 1,25D in muscle, results in the rapid activation of Raf-1 by the phosphorylation of its serine residue, which relies on the involvement of Ras and PKC-α (142, 143).

Raf-1 then leads to the activation of MAPK kinase, which activates ERK1/2, after which the phosphorylation of a range of proteins and transcription factors including cAMP response element-binding protein and Elk-1 and the increased expression of other proteins relevant to cell proliferation and differentiation, namely c-myc and c-fos, take place (144, 145).

Another MAPK activated by 1,25D in cultured myoblasts is p38. Rapid c-Src-dependent stimulation of MAPK kinases MKK3 and 6 and p38 was demonstrated in C2C12 myoblasts after treatment with 1,25D (146). After this, p38-dependent activation of MAPK2 and subsequent phosphorylation of heat-shock protein 27 was demonstrated. Heat-shock protein 27 has an important role through its association with the actin microfilament system and cytoskeletal remodeling of muscle cells (146, 147). More recently, 1,25D-mediated AKT phosphorylation in differentiating C2C12 cells was also shown to occur via c-Src, p38, MAPK and phosphoinositide-3 kinase pathways (148).

Although little is known about its exact activity in this context, a third member of the MAPK family, namely c-Jun N-terminal kinase-1/2, is also phosphorylatively activated by 1,25D in C2C12 myoblasts (146). Therefore, an intricate system of nongenomic regulatory responses to 1,25D may control cellular proliferation and differentiation of muscle cells, although the relative role of each component remains unclear.

A variety of genomic responses to 1,25D have also recently been elucidated. Apart from being the first to describe the presence of VDR within muscle cells, Simpson et al. (25) also demonstrated dose-dependent reduction in the proliferation of G-8 myoblast cells that were treated with 1,25D and a commensurate reduction in DNA synthesis, suggesting that genomic responses to 1,25D gave rise to the down-regulation in myoblast proliferation and enhanced differentiation into myotubes.

In a recent study, treatment of C2C12 myoblasts with 1,25D for 7 d as opposed to vehicle resulted in increased mRNA and protein expression of transcription factors known to enhance myogenesis, namely myogenic differentiation antigen, desmin, myogenin, and IGF-II and the reduced expression of proliferating cell nuclear antigen and myostatin, which, respectively, enhance cell proliferation and negatively regulate muscle mass (118). Morphologically, cells treated with 1,25D for 10 d displayed significantly increased muscle fiber size and diameter, as indicated by staining for MHC type II a late myogenic marker. These changes were associated with VDR-induced genomic mechanisms as evidenced by significant increases in the expression of the receptor by 1 d of 1,25D treatment and its nuclear translocation at 4 d as opposed to its persistent location in the cytoplasm of cells treated with vehicle.

However, these findings stand in contrast to an earlier report that described the down-regulation of myogenin and myogenic transcription factor 5 (myf5) at an mRNA level in C2C12 myoblasts treated with 1,25D for 48 and 96 h compared with those treated with vehicle (21). Furthermore, this coincided with the reduced expression of neonatal forms of MHC, suggesting myoblast maturation in cells treated with 1,25D. It is possible that differences in study design may have accounted for these contradictory findings, specifically pertaining to myogenin expression. Different durations of treatment, and daily vs. single treatment regimens were employed in these studies (21, 118).

In another study Artaza and Norris (390), vitamin D treatment of mesenchymal stem cells resulted in increased expression of follistatin, an antagonist of myostatin, and caused down-regulation of TGF-β. These vitamin D-mediated changes in gene expression imply that it has a potential role in the inhibition of fibrosis and, perhaps, the promotion of myogenesis and osteogenesis in mesenchymal stem cells.

In a recent study, European sea bass treated with various doses of dietary cholecalciferol from 9–44 d after hatching demonstrated dose-dependent effects in the gene expression of a number of myogenic transcription factors and dose-dependent increases in white muscle fiber size and number (149).

Although vitamin D has clear effects on muscle differentiation, more research is needed to elucidate the nature of these mechanisms. It is also important to note that the overlapping functions and complex regulatory pathways determining the activity of myogenic transcription factors are themselves something of a mystery although recently reviewed in detail (150).

E. Muscle contractile proteins

There is evidence that vitamin D may play a role in the regulation of key components in the cytoskeletal structure of muscle cells. As discussed in Section II.B, the complex interaction between actin and myosin, two cytoskeletal proteins, forms the basis of understanding muscle contraction (Fig. 5). Similar proteins play a potential role in intracellular trafficking and, potentially, GLUT4 translocation.

Significant reductions in components of the actomyosin-troponin complex in the skeletal muscle of vitamin D-deficient rats and rabbits have been reported in two separate studies, although in the latter, this may not have been directly related to 1,25D because in vivo administration of ethane-1-hydroxy-1,1-diphosphate in doses known to inhibit 1,25D had no effect on these components of the cytoskeleton (151, 152). A study also reported an increase in the muscle concentrations of actin and troponin C in chicks replete with vitamin D as opposed to their vitamin D-deficient counterparts (141). Taken together, these reports suggest a direct role for 25D in the up-regulation of these muscle contractile proteins (141, 151). Furthermore, the direct role of 25D in phosphate homeostasis, as discussed, and the recent demonstration of direct binding between 25D and the alternative pocket of the VDR with subsequent biological effects in COS-1 kidney cells suggest that reconsideration of the ability of 25D to generate biological responses in vivo may be in order (123).

F. Phospholipid composition

Phospholipids, a class of lipids that reside within the cell membrane, have been implicated in a variety of signal transduction pathways, including insulin signaling and calcium handling, and play a role in cell membrane function including caveolae. Alterations in phospholipid composition have been associated with insulin-resistant states (153). There is also evidence of a direct role of 1,25D in the regulation of the phospholipid metabolic pathway.

A study reported higher relative concentrations of phospholipids in the muscle SR membranes of vitamin D-replete vs. -deficient animals (141). There were also significant changes in the levels of particular phospholipids, specifically an increased concentration of phosphatidylcholine and decreases in phosphatidylethanolamine, in the sarcolemma vesicles of vitamin D-replete vs. -deficient chicks (141). Another study suggested that 1,25D treatment led to the activation of specific methylation pathways that leads to the conversion of phosphatidylethanolamine to phosphatidylcholine in muscle cells (154). This is likely to represent a genomic effect as 1,25D-mediated binding of [³H]glycerol and [¹⁴C]ethanolamine to phosphatidylcholine in cultured myoblasts was inhibited by the action of actinomycin D, an inhibitor of DNA synthesis. Although the precise significance of genomic 1,25D-mediated influences on phospholipid composition remains uncertain, potential influences on calcium handling, cell proliferation, and insulin signaling merit further consideration.

G. Bone-muscle cross talk and vitamin D

It is well established that muscle strength and muscle mass are important determinants of bone density, bone geometry, and fracture risk. Vitamin D therefore plays a key role in bone metabolism not only through its direct effects mediated by the VDR in osteoblasts and its effects on calcium absorption by the intestines but also through its effects on muscle fiber size and muscle function noted above. Interestingly, during growth, serum 25D levels have been found to be negatively associated with the accrual of bone mineral content in girls (155), and 25D levels decrease as lean mass increases (156). These observations raise the possibility that muscle tissue may require additional vitamin D during growth and that an important function of vitamin D on bone mass accrual may be mediated by the effects of vitamin D on accumulation of lean mass, which has been documented to precede gains in bone (157).

Another pertinent consideration is the role of FGF23, a protein whose regulation is closely linked to phosphate homeostasis and the activation of vitamin D (step 3, Fig. 2). Although 1,25D up-regulates the expression of FGF23 by osteocytes and osteoblasts, FGF23 inhibits 1,25D synthesis and stimulates its breakdown (158). Therefore, FGF23 excess, as seen in those with oncogenic or X-linked hypophosphatemic osteomalacia, leads to reduced 1,25D and phosphate levels and is also associated with muscle weakness. In Hyp mice, a model of X-linked hypophosphatemic rickets, the administration of neutralizing FGF23 antibodies increased 1,25D and phosphate levels as well as leading to improvements in grip strength and spontaneous movement (159). Therefore, the FGF23-vitamin D feedback loop presents another layer of complexity when assessing effects on muscle function.

H. Cell models and molecular pathways for insulin signaling and diabetes

1. Insulin signaling in cell models

Treatment of U-937 human promonocytic cells with 1,25D leads to time- and dose-dependent increases in the mRNA expression of insulin receptors, as shown in two separate studies (160, 161). In the second study, 1,25D treatment also resulted in an increase in VDR expression, suggesting that the accompanying increases in insulin-mediated [¹⁴C]2-deoxyglucose uptake and [¹²⁵I]insulin binding in these cells resulted from the activation of genomic pathways. The authors also reported a putative VDRE in the human insulin receptor gene promoter on the basis of luciferase assays on transfected plasmid constructs (162). However, differences in insulin signaling mechanisms between skeletal muscle and immune cells, with the reliance of the latter on GLUT1 rather than GLUT4 transporters for glucose uptake, may limit extrapolation of these results.

In a recent study, differentiated C2C12 muscle cells were rendered insulin resistant and atrophic by treatment with free fatty acids (FFA) (163). However, coadministration of 1,25D with FFA resulted in significant dose- and time-dependent increases in the insulin-mediated uptake of [³H]2-deoxyglucose compared with cells that had received FFA alone. This effect of 1,25D was initially observed at 12 h and reached stability at 36 h, at which point complete reversal of the FFA-mediated insulin resistance was observed (using 10 nm 1,25D). In addition, 1,25D treatment prevented muscle atrophy as demonstrated by significantly increased myotube diameter in cells that had been cotreated with 1,25D and FFA as opposed to those receiving FFA alone.

To account for these effects on insulin resistance, the authors reported that 1,25D treatment reversed a number of FFA-induced abnormalities in the insulin-signaling pathway. At a protein level, 1,25D significantly inhibited FFA-induced serine phosphorylation of IRS-1 and increased the tyrosine phosphorylation of IRS-1 and the phosphorylation of Akt. In addition, the FFA-mediated activation of c-Jun N-terminal kinase, a protein with a significant role in insulin resistance, was significantly reversed by 1,25D treatment. Thus, this report provided the first demonstration of a direct effect of 1,25D in the restoration of key components of the insulin-signaling pathway in an established cellular model of insulin resistance.

2. Arachidonic acid (AA) release

Apart from direct effects on the composition of membrane phospholipids as discussed earlier, there is evidence that 1,25D leads indirectly to the release of AA by a process involving deacylation of membrane-bound phosphatidylcholine (164). This is relevant because levels of AA, a polyunsaturated fatty acid, in skeletal muscle correlate inversely with insulin resistance in humans. AA may also modulate the function of membrane insulin receptors and glucose transporters and may influence the action of insulin by acting as a precursor for the generation of second messengers such as DAG (90). AA also plays a central role in inflammation, with the production of both pro- and antiinflammatory metabolites that may also have potential effects on insulin signaling.

In chick myoblasts, 1,25D treatment resulted in dose-dependent increases in the release of [³H]AA, but the effect appeared to be dependent on the influx of extracellular calcium and the indirect activation of phospholipase A₂ by PKC (164). More research is needed to clarify the possibilities that arise from an effect of 1,25D on AA release and its availability for intracellular processes.

3. Caveolin-I mediated insulin sensitivity

Some data suggests that vitamin D may play a role in caveolin-I mediated insulin sensitivity (165). Caveolin-I, a scaffolding protein within the caveolar membrane, has recently been shown to play an important role in insulin sensitivity. Its selective down-regulation in the skeletal muscle of wild-type mice and its reduced expression in JYD mice, an age-dependent type 2 diabetes model, were associated with significant impairments in insulin sensitivity (166). VDR is present within the caveolae, appear in close proximity to caveolin-1 on confocal microscopy after treatment of ROS 17/2.8 cells with 1,25D (110) and relies on caveolin-I for the mediation of nongenomic effects within skeletal muscle cells (20), all supporting a close association between vitamin D and caveolin-I and raising the question as to whether vitamin D might also have an impact on caveolin-I mediated insulin sensitivity.

Perhaps the strongest evidence to support this possibility is the combination of marked insulin resistance and vitamin D resistance in humans with homozygous nonsense caveolin-1 mutations, otherwise known as Berardinelli-Seip congenital lipodystrophy (167). Future research may address this intriguing conceptual link.

IV. Vitamin D and Muscle: Studies in Animal Models

A. VDRKO mice

The VDRKO mouse model has provided valuable insights into the biological function of the vitamin D endocrine system and, specifically, the genomic activity of the transcription factor VDR (13). The role of vitamin D in the development, morphology, and function of skeletal muscle has been made clearer by studies on this mouse model.

The earliest form of the VDRKO mouse, generated by targeted ablation of the DNA encoding the second zinc finger of the DNA-binding domain, was described in 1997 (28). Mice appeared phenotypically normal at birth, despite known expression of the VDR in fetal life in wild-type mice, but became hypocalcemic with secondary hyperparathyroidism around weaning (21 d) and developed alopecia associated with large dermal cysts by 4 wk of age and rickets and growth retardation by d 35. The initial lack of hypocalcemia is considered to be due to the early presence of nonsaturable 1,25D-independent mechanisms of intestinal calcium absorption. However, when 1,25D-dependent mechanisms take over, mice require a high calcium (2%), phosphorus (1.25%), and lactose (20%) rescue diet for survival. The alopecia is interesting, because people with mutations in VDR (vitamin D-resistant rickets) also develop alopecia (168, 169).

1. Muscle morphology and development

A study in 2003 described histological changes in the muscles of VDRKO mice directly before and after the development of hypocalcemia. At 3 wk of age, samples taken from the quadriceps muscle of VDRKO mice displayed a wider degree of variability in fiber diameter in addition to significant reductions in the size of both type I and II fibers compared with those in wild-type mice (21). By 8 wk of age, generalized atrophy of type I and II muscle fibers had worsened in the VDRKO mice, suggesting progression due to the absence of the VDR or the additional effect of systemic biochemical changes that had not been present at 3 wk. These changes were also reported in VDRKO mice on a high-calcium, -phosphorus, and -lactose rescue diet, suggesting that the absence of VDR was the predominant cause rather than systemic biochemical changes. Neither degenerative nor necrotic changes were observed in VDRKO skeletal muscle, and similar results were obtained in a range of other muscle groups in this model, suggesting a diffuse effect of the VDR on skeletal muscle morphology.

Impaired regulation in the expression of particular myogenic transcription factors, known to control muscle phenotype, was reported as an explanation for these findings. On immunohistochemistry, Northern blot, and RT-PCR analyses, the expression of myf5, myogenin, and E2A was significantly higher in quadriceps samples of 3- and 8-wk-old VDRKO mice compared with age-matched wild-type mice. Persistent expression of immature forms of MHC was also found in the small muscle fibers of VDRKO mice but not in their type II muscle fibers. The expression of two other myogenic transcription factors, namely MyoD and MRF4, were not particularly affected in VDRKO mice.

Although these data support a role for vitamin D in the regulation of muscle development, precise genomic mechanisms by which the VDR influences myogenesis are unclear, and the issue is further complicated by the failure to identify negative VDRE in the promoter region of the genes encoding myf5 and myogenin (170, 171).

2. Muscle strength and functional assessment

A number of studies have examined muscle strength and performance in VDRKO mice. These investigations rarely assess muscle function in isolation, with results being potentially influenced by a range of other factors including cardiovascular endurance, balance, and the ability to learn new skills. Furthermore, behavioral differences between VDRKO and wild-type mice have been reported, which may confound the assessment of some tests (172). Nevertheless, these studies provide an indication of the functional motor deficits associated with loss of VDR by testing swimming ability and motor coordination.

a. Forced swim test analysis.

Three studies have described differences in the swimming behavior of VDRKO mice. In one study comparing six VDRKO mice with 10 wild-type and heterozygote mice that were shaved to account for alopecia-related alterations in buoyancy, severe impairment of swimming was seen in the knockout mice (173). Baseline levels of locomotor, sensory, and vestibular activity were similar. On swim testing, they were observed to swim in a predominantly vertical position, had a significantly greater number of sinking episodes, and displayed stereotypic rotations and catatonic-like upper limb spasms.

In another study, a significantly greater number of sinking episodes were seen among eight VDRKO mice compared with six wild-type controls (174). However, on being given a stimulus, they showed no impairment in ability to move down a 1-m laneway or in reaching a visible platform. However, VDRKO mice did display greater fatigue after the swim based upon differences in rearing and grooming behavior. The authors hypothesized that this was due to the reduced availability of calcium in VDRKO mice after exercise.

A third study reported that abnormal patterns of swimming behavior among VDRKO mice were more marked in older (5–13 months) rather than younger knockouts (175). Interestingly, no such impairment in swimming ability was seen among a group of 11 1α-hydroxylase (Cyp27B1)-knockout mice (175). That suggests the intriguing possibility that there might be vitamin D-independent effects of VDR upon muscle function (175).

b. Tests of motor coordination.

The time taken for a mouse to fall off a device that rotates at fixed speeds and in acceleration is considered to indicate its degree of motor coordination (174). In one study, VDRKO mice stayed on a rotating device for a significantly shorter time than wild-type mice on both the accelerating and fixed-speed rotarod tests (174). On gait assessment, VDRKO mice took significantly shorter steps and traveled a shorter distance than wild-type mice when placed in an open field for 5 min.

Significantly shorter retention times on accelerated rotarod testing were confirmed in another group of 12-month-old VDRKO mice compared with age-matched wild-type mice (175). These 12-month-old mice demonstrated similar impairments in muscle coordination in tilting box and tilting tube tests, which measure the latency and the angle at which the animal displaces off a device that, respectively, tilts or rotates at different angles. However, no differences were found in 6-month-old VDRKO mice.

In another study, the vertical screen test that measures the time taken for a mouse to fall from a screen that becomes suddenly vertical while the mouse rests on it in a horizontal position (i.e. retention time) was employed (173). VDRKO mice demonstrated markedly shorter retention times compared with both wild-type and heterozygous groups, implying impaired motor coordination or strength.

In summary, VDRKO mice demonstrate notable defects in their overall motor performance with significant impairments in their ability to remain afloat while swimming and shorter stride length and impaired motor coordination and balance on rotarod, rotating tube, and tilting box tests. Although the effect of alopecia was accounted for in one study, other biochemical and behavioral changes in VDRKO mice together with the widespread expression of the VDR in the central nervous system, vestibular system, and spinal cord under normal conditions make direct assessment of its role in muscle function difficult in this setting (175). Nevertheless, it is clear that the overall motor function of these mice is impaired and that further work is needed to clarify the individual components that may account for this.

B. Other animal models

Although the VDRKO mouse model has provided valuable insights into the biological activity of vitamin D, it is more accurate to consider this as a model of type II vitamin D-dependent rickets rather than vitamin D deficiency. Studies have examined muscle function in animals rendered vitamin D deficient by a range of dietary and other methods (176). In a study from 1978, vitamin D-deficient male Sprague-Dawley rats demonstrated significantly prolonged times to peak tension and recovery times in electrically stimulated soleus muscle contraction compared with vitamin D-replete rats on normal chow (177). These changes normalized after vitamin D repletion. In contrast, no impairments were noted in rats rendered phosphate deficient or calcium deficient 10 d before experimentation.

A study from 1979 examined muscle function in chicks raised from hatching on a vitamin D-deficient diet (178). Significant reductions in the tension generated by the triceps surae during stimulation of the posterior tibial nerve compared with that in vitamin D-replete chicks were found. This occurred independently of calcium and phosphate levels. The authors found no difference in the histological appearance of muscle samples but did isolate reduced muscle mitochondrial calcium levels. This was independent of serum calcium levels and was proposed as the mechanism by which vitamin D deficiency affected muscle contraction force.

Four weeks after the commencement of a vitamin D-deficient diet, rats displayed marked skeletal muscle hypersensitivity on calf compression compared with those fed a normal diet (179). This finding was not related to hypocalcemia but was rather accelerated by increased dietary calcium and was accompanied by early impairments in balance on a beam-walk test to assess the frequency of foot slips. Histologically, vitamin D-deficient rats displayed increased numbers of presumptive nocioceptor axons in skeletal muscle, providing an explanation for their hyperalgesic phenotype.

In contrast to these studies, a recent report questioned the primary role of vitamin D, rather than biochemical changes associated with vitamin D deficiency, in resulting in myopathy (176). In 58 male Wistar rats that were rendered vitamin D, phosphorus, and calcium deficient by dietary methods and housing under incandescent lighting, muscle strength of the soleus as assessed by a force transducer detecting isometric contraction was significantly reduced compared with that in replete controls (176). The authors concluded that phosphorus deficiency was the primary culprit on the basis of several findings. These included a direct independent correlation between phosphorus levels and the reduction in soleus muscle force in these animals, complete restoration in slow-twitch muscle force after dietary repletion with phosphorus despite persistent vitamin D deficiency and similar measures of muscle function among phosphorus-replete rats that were either vitamin D deficient or replete. Similarly, there was no difference in muscle contraction among rats that were calcium deficient and replete, in which vitamin D and phosphorus levels were within the reference range. The central importance of phosphorus in the production of ATP, essential for muscle contraction, was considered as the explanation for these findings.

Therefore, the difficulty in differentiating the effects of severe vitamin D deficiency from those of hypocalcemia and hypophosphatemia in the development of muscle pathology is common to animal and human clinical studies. However, cell lines and tissue culture enable study of direct effects, and these studies date back to the 1970s.

C. Animal studies on insulin sensitivity and diabetes

Although vitamin D deficiency has been associated with more aggressive disease among nonobese diabetic mice (180), a model for type 1 diabetes, few animal trials have addressed the role of vitamin D in insulin resistance. In one study of ob/ob mice, an obese type 2 diabetes model, significant improvements in hyperglycemia and hyperinsulinemia in response to treatment with 1α-hydroxyvitamin D₃ (1α-OHD₃) were observed (181). In another study of aged rats with type 2 diabetes and insulin resistance that received 25D, 1α-OHD₃, or no treatment, serum 1,25D levels correlated positively with the glucose infusion rate on euglycemic clamp studies at the end of the 12-wk treatment period (182), suggesting a potential role in insulin sensitivity. However, the main focus of this study was the demonstration of bone loss among insulin-resistant rats attributed to a reduction in their renal 1α-hydroxylase activity.

D. Summary: vitamin D and muscle function in animal studies

Congenital absence of the VDR in VDRKO mice is associated with atrophy of both type I and type II fibers, poor musculoskeletal performance in behavioral tests, and marked changes in gait. Vitamin D deficiency induced in rats has also been found to alter muscle function when compared with vitamin D-replete animals. Together, these studies using animal models provide additional evidence that vitamin D plays an important role in muscle physiology. However, they do not separate the effects of muscle vs. whole-body deletion of VDR. Biochemical abnormalities in these mouse models may once again confound these findings (Fig. 4). A similar question has been recently answered in relation to cardiac muscle; mice with specific deletion of VDR in cardiac muscle displayed significant cardiac hypertrophy, similar to that seen in whole-body VDRKO mice (183). Specific deletion of VDR in skeletal muscle using Cre-Lox technology will be required to clarify this question.

V. VDR Polymorphisms and Muscle Function

Several single-nucleotide polymorphisms (SNP) in the gene encoding the VDR have been associated with a range of phenotypic characteristics including muscle strength. These have been summarized in Table 3.

Table 3.

Studies assessing the relation between VDR polymorphisms, falls, muscle function, and markers of insulin sensitivity

Study (Ref.) other	n, Sex, Age	Polymorphisms and groups	Outcome and adjustments	Findings and effects
Studies of muscle strength or function
Barr et al. (359)	3145	BsmI	Falls (self-reported)	More falls OR 1.5 (1.01–2.3)
APOSS	F, 54	BB, Bb vs. bb	Adj: age, Ht, Wt, 25D, month
OPUS	2374	BsmI	Falls, leg force, STST	More falls, ↓STST
	F, 67	BB, Bb vs. bb	Adj: age, Ht, Wt, 25D, month	OR = 1.3 (1.03–1.6)
Geusens et al. (189)	121	BsmI	Quadriceps strength	Stronger by 23%
Normal	F, >70	bb vs. BB	Adj: age, calcium, BMD
Obese	380	BsmI	Quadriceps strength	No difference
	F, >70	bb vs. BB	Adj: age, calcium, BMD
Windelinckx et al. (187)
Female	240	FokI	Knee force	No difference
	F, 42	FF,Ff vs. Ff vs. ff	Adj: age, Ht, FFM
Male	253 M, 55	BsmI + TaqI: BB+tt vs. tt vs. b/T	Quadriceps strength Adj: age, Ht, FFM	Stronger P = 0.01
Roth et al. (185)	302, M 58–93	FokI	FFM, Grip, AMM	Reduced FFM
Caucasian		FF vs. Ff /ff	Adj: age, fat, activity
Onder et al. (193)	259	BsmI	Falls	Decreased falls
CommD	M, F, >80	BB/Bb vs. bb	Adj: age, sex, ADL, co-morbidities	OR = 0.14 (0.03–0.66)
Hopkinson et al. (186)	211	FokI	Quadriceps strength	Weaker in all (41 vs. 46 kg)
107 COPD,	M, F	FF vs. Ff and ff	Adj: age, sex, FFM, ACE
104 Normal	∼62	BsmI bb/ Bb vs. BB	Quadriceps strength	Stronger in COPD
Grundberg et al. (190)	175	BsmI BB vs. bb	Hamstring strength, FFM	Both lower
	F, 20–39		Adj: age, fat mass, FFM	HS: r = −0.18
		Polyadenosine repeat LL vs. ss	Hamstring strength, FFM Adj: nil	Trend lower
Bahat et al. (192)     Turkish	120 M, >65	BsmI BB vs. bb	Quadriceps and hamstring strength, knee torque	Weaker
			Adj:Nil
Wang et al. (191)	109	BsmI: BB vs. bb	Hamstring strength	Lower: 11%
Chinese	F, 21	ApaI: AA vs. aa /Aa	Adj: nil	Lower: 29%
Studies of diabetes and glucose homeostasis
Oh and Barrett-Connor (360)	1545	BsmI: bb vs. BB	HOMA-IR	↑HOMA, normal
242 DM	M, F, 72		Adj: nil
		ApaI: aa vs. AA	T2D incidence. Adj: nil	↑T2D
			FPG, IGT Adj: nil	↑FPG, ↑IGT
Ortlepp et al. (361)	1539	BsmI	FPG	0.2 mm ↑FPG in less active ♂
Aircrew	M, F, 33	BB vs. Bb or bb	Adj: nil
Malecki et al. (362)	548	FokI, ApaI, BsmI, TaqI	T2D	No differences
Polish 308 T2D	M, F,		Adj: nil
Ye et al. (363)	452	TaqI TT vs. Tt/tt	BMI at onset T2D	BMI 29 vs. 32
309 T2D	M, F, 62		Adj: nil
		BsmI, Tru9I, ApaI	T2D Adj: nil	No association
Bid et al. (364)	260	Foki, BsmI, TaqI	T2D	FFBbTt OR = 4.0 (0.6–24.7)
Indian 100 T2D	M, F, 49	Combinations	Adj: nil
Speer et al. (365)	216, M, F	BsmI	Postprandial C-peptide	↑C-peptide in T2DM and obese
29 T2D	18–83	BB vs. Bb and bb	Adj: nil
Filus et al. (366)	176, M, 52	FokI: FF/Ff vs. ff	Fasting insulin. Adj: nil	↑insulin
Polish		BsmI: BB vs. bb	BMI Adj: nil	↑BMI

Study (Ref.) other	n, Sex, Age	Polymorphisms and groups	Outcome and adjustments	Findings and effects
Studies of muscle strength or function
Barr et al. (359)	3145	BsmI	Falls (self-reported)	More falls OR 1.5 (1.01–2.3)
APOSS	F, 54	BB, Bb vs. bb	Adj: age, Ht, Wt, 25D, month
OPUS	2374	BsmI	Falls, leg force, STST	More falls, ↓STST
	F, 67	BB, Bb vs. bb	Adj: age, Ht, Wt, 25D, month	OR = 1.3 (1.03–1.6)
Geusens et al. (189)	121	BsmI	Quadriceps strength	Stronger by 23%
Normal	F, >70	bb vs. BB	Adj: age, calcium, BMD
Obese	380	BsmI	Quadriceps strength	No difference
	F, >70	bb vs. BB	Adj: age, calcium, BMD
Windelinckx et al. (187)
Female	240	FokI	Knee force	No difference
	F, 42	FF,Ff vs. Ff vs. ff	Adj: age, Ht, FFM
Male	253 M, 55	BsmI + TaqI: BB+tt vs. tt vs. b/T	Quadriceps strength Adj: age, Ht, FFM	Stronger P = 0.01
Roth et al. (185)	302, M 58–93	FokI	FFM, Grip, AMM	Reduced FFM
Caucasian		FF vs. Ff /ff	Adj: age, fat, activity
Onder et al. (193)	259	BsmI	Falls	Decreased falls
CommD	M, F, >80	BB/Bb vs. bb	Adj: age, sex, ADL, co-morbidities	OR = 0.14 (0.03–0.66)
Hopkinson et al. (186)	211	FokI	Quadriceps strength	Weaker in all (41 vs. 46 kg)
107 COPD,	M, F	FF vs. Ff and ff	Adj: age, sex, FFM, ACE
104 Normal	∼62	BsmI bb/ Bb vs. BB	Quadriceps strength	Stronger in COPD
Grundberg et al. (190)	175	BsmI BB vs. bb	Hamstring strength, FFM	Both lower
	F, 20–39		Adj: age, fat mass, FFM	HS: r = −0.18
		Polyadenosine repeat LL vs. ss	Hamstring strength, FFM Adj: nil	Trend lower
Bahat et al. (192)     Turkish	120 M, >65	BsmI BB vs. bb	Quadriceps and hamstring strength, knee torque	Weaker
			Adj:Nil
Wang et al. (191)	109	BsmI: BB vs. bb	Hamstring strength	Lower: 11%
Chinese	F, 21	ApaI: AA vs. aa /Aa	Adj: nil	Lower: 29%
Studies of diabetes and glucose homeostasis
Oh and Barrett-Connor (360)	1545	BsmI: bb vs. BB	HOMA-IR	↑HOMA, normal
242 DM	M, F, 72		Adj: nil
		ApaI: aa vs. AA	T2D incidence. Adj: nil	↑T2D
			FPG, IGT Adj: nil	↑FPG, ↑IGT
Ortlepp et al. (361)	1539	BsmI	FPG	0.2 mm ↑FPG in less active ♂
Aircrew	M, F, 33	BB vs. Bb or bb	Adj: nil
Malecki et al. (362)	548	FokI, ApaI, BsmI, TaqI	T2D	No differences
Polish 308 T2D	M, F,		Adj: nil
Ye et al. (363)	452	TaqI TT vs. Tt/tt	BMI at onset T2D	BMI 29 vs. 32
309 T2D	M, F, 62		Adj: nil
		BsmI, Tru9I, ApaI	T2D Adj: nil	No association
Bid et al. (364)	260	Foki, BsmI, TaqI	T2D	FFBbTt OR = 4.0 (0.6–24.7)
Indian 100 T2D	M, F, 49	Combinations	Adj: nil
Speer et al. (365)	216, M, F	BsmI	Postprandial C-peptide	↑C-peptide in T2DM and obese
29 T2D	18–83	BB vs. Bb and bb	Adj: nil
Filus et al. (366)	176, M, 52	FokI: FF/Ff vs. ff	Fasting insulin. Adj: nil	↑insulin
Polish		BsmI: BB vs. bb	BMI Adj: nil	↑BMI

Each section is listed in order of number of participants, highest to lowest. ACE, Angiotensin converting enzyme genotype; Adj, adjustments; AMM, appendicular muscle mass; ADL, activities of daily living; APOSS, Aberdeen Prospective Osteoporosis Screening Study; COPD, chronic obstructive pulmonary disease; F, female; FFM, fat-free mass; FPG, fasting plasma glucose; Ht, height; IGT, impaired glucose tolerance; M, male; N, normal group; OPUS, Osteoporosis and Ultrasound Study; OR, odds ratio; PP, postprandial; T2D, type 2 diabetes mellitus; Wt, weight.

Table 3.

Studies assessing the relation between VDR polymorphisms, falls, muscle function, and markers of insulin sensitivity

Study (Ref.) other	n, Sex, Age	Polymorphisms and groups	Outcome and adjustments	Findings and effects
Studies of muscle strength or function
Barr et al. (359)	3145	BsmI	Falls (self-reported)	More falls OR 1.5 (1.01–2.3)
APOSS	F, 54	BB, Bb vs. bb	Adj: age, Ht, Wt, 25D, month
OPUS	2374	BsmI	Falls, leg force, STST	More falls, ↓STST
	F, 67	BB, Bb vs. bb	Adj: age, Ht, Wt, 25D, month	OR = 1.3 (1.03–1.6)
Geusens et al. (189)	121	BsmI	Quadriceps strength	Stronger by 23%
Normal	F, >70	bb vs. BB	Adj: age, calcium, BMD
Obese	380	BsmI	Quadriceps strength	No difference
	F, >70	bb vs. BB	Adj: age, calcium, BMD
Windelinckx et al. (187)
Female	240	FokI	Knee force	No difference
	F, 42	FF,Ff vs. Ff vs. ff	Adj: age, Ht, FFM
Male	253 M, 55	BsmI + TaqI: BB+tt vs. tt vs. b/T	Quadriceps strength Adj: age, Ht, FFM	Stronger P = 0.01
Roth et al. (185)	302, M 58–93	FokI	FFM, Grip, AMM	Reduced FFM
Caucasian		FF vs. Ff /ff	Adj: age, fat, activity
Onder et al. (193)	259	BsmI	Falls	Decreased falls
CommD	M, F, >80	BB/Bb vs. bb	Adj: age, sex, ADL, co-morbidities	OR = 0.14 (0.03–0.66)
Hopkinson et al. (186)	211	FokI	Quadriceps strength	Weaker in all (41 vs. 46 kg)
107 COPD,	M, F	FF vs. Ff and ff	Adj: age, sex, FFM, ACE
104 Normal	∼62	BsmI bb/ Bb vs. BB	Quadriceps strength	Stronger in COPD
Grundberg et al. (190)	175	BsmI BB vs. bb	Hamstring strength, FFM	Both lower
	F, 20–39		Adj: age, fat mass, FFM	HS: r = −0.18
		Polyadenosine repeat LL vs. ss	Hamstring strength, FFM Adj: nil	Trend lower
Bahat et al. (192)     Turkish	120 M, >65	BsmI BB vs. bb	Quadriceps and hamstring strength, knee torque	Weaker
			Adj:Nil
Wang et al. (191)	109	BsmI: BB vs. bb	Hamstring strength	Lower: 11%
Chinese	F, 21	ApaI: AA vs. aa /Aa	Adj: nil	Lower: 29%
Studies of diabetes and glucose homeostasis
Oh and Barrett-Connor (360)	1545	BsmI: bb vs. BB	HOMA-IR	↑HOMA, normal
242 DM	M, F, 72		Adj: nil
		ApaI: aa vs. AA	T2D incidence. Adj: nil	↑T2D
			FPG, IGT Adj: nil	↑FPG, ↑IGT
Ortlepp et al. (361)	1539	BsmI	FPG	0.2 mm ↑FPG in less active ♂
Aircrew	M, F, 33	BB vs. Bb or bb	Adj: nil
Malecki et al. (362)	548	FokI, ApaI, BsmI, TaqI	T2D	No differences
Polish 308 T2D	M, F,		Adj: nil
Ye et al. (363)	452	TaqI TT vs. Tt/tt	BMI at onset T2D	BMI 29 vs. 32
309 T2D	M, F, 62		Adj: nil
		BsmI, Tru9I, ApaI	T2D Adj: nil	No association
Bid et al. (364)	260	Foki, BsmI, TaqI	T2D	FFBbTt OR = 4.0 (0.6–24.7)
Indian 100 T2D	M, F, 49	Combinations	Adj: nil
Speer et al. (365)	216, M, F	BsmI	Postprandial C-peptide	↑C-peptide in T2DM and obese
29 T2D	18–83	BB vs. Bb and bb	Adj: nil
Filus et al. (366)	176, M, 52	FokI: FF/Ff vs. ff	Fasting insulin. Adj: nil	↑insulin
Polish		BsmI: BB vs. bb	BMI Adj: nil	↑BMI

Study (Ref.) other	n, Sex, Age	Polymorphisms and groups	Outcome and adjustments	Findings and effects
Studies of muscle strength or function
Barr et al. (359)	3145	BsmI	Falls (self-reported)	More falls OR 1.5 (1.01–2.3)
APOSS	F, 54	BB, Bb vs. bb	Adj: age, Ht, Wt, 25D, month
OPUS	2374	BsmI	Falls, leg force, STST	More falls, ↓STST
	F, 67	BB, Bb vs. bb	Adj: age, Ht, Wt, 25D, month	OR = 1.3 (1.03–1.6)
Geusens et al. (189)	121	BsmI	Quadriceps strength	Stronger by 23%
Normal	F, >70	bb vs. BB	Adj: age, calcium, BMD
Obese	380	BsmI	Quadriceps strength	No difference
	F, >70	bb vs. BB	Adj: age, calcium, BMD
Windelinckx et al. (187)
Female	240	FokI	Knee force	No difference
	F, 42	FF,Ff vs. Ff vs. ff	Adj: age, Ht, FFM
Male	253 M, 55	BsmI + TaqI: BB+tt vs. tt vs. b/T	Quadriceps strength Adj: age, Ht, FFM	Stronger P = 0.01
Roth et al. (185)	302, M 58–93	FokI	FFM, Grip, AMM	Reduced FFM
Caucasian		FF vs. Ff /ff	Adj: age, fat, activity
Onder et al. (193)	259	BsmI	Falls	Decreased falls
CommD	M, F, >80	BB/Bb vs. bb	Adj: age, sex, ADL, co-morbidities	OR = 0.14 (0.03–0.66)
Hopkinson et al. (186)	211	FokI	Quadriceps strength	Weaker in all (41 vs. 46 kg)
107 COPD,	M, F	FF vs. Ff and ff	Adj: age, sex, FFM, ACE
104 Normal	∼62	BsmI bb/ Bb vs. BB	Quadriceps strength	Stronger in COPD
Grundberg et al. (190)	175	BsmI BB vs. bb	Hamstring strength, FFM	Both lower
	F, 20–39		Adj: age, fat mass, FFM	HS: r = −0.18
		Polyadenosine repeat LL vs. ss	Hamstring strength, FFM Adj: nil	Trend lower
Bahat et al. (192)     Turkish	120 M, >65	BsmI BB vs. bb	Quadriceps and hamstring strength, knee torque	Weaker
			Adj:Nil
Wang et al. (191)	109	BsmI: BB vs. bb	Hamstring strength	Lower: 11%
Chinese	F, 21	ApaI: AA vs. aa /Aa	Adj: nil	Lower: 29%
Studies of diabetes and glucose homeostasis
Oh and Barrett-Connor (360)	1545	BsmI: bb vs. BB	HOMA-IR	↑HOMA, normal
242 DM	M, F, 72		Adj: nil
		ApaI: aa vs. AA	T2D incidence. Adj: nil	↑T2D
			FPG, IGT Adj: nil	↑FPG, ↑IGT
Ortlepp et al. (361)	1539	BsmI	FPG	0.2 mm ↑FPG in less active ♂
Aircrew	M, F, 33	BB vs. Bb or bb	Adj: nil
Malecki et al. (362)	548	FokI, ApaI, BsmI, TaqI	T2D	No differences
Polish 308 T2D	M, F,		Adj: nil
Ye et al. (363)	452	TaqI TT vs. Tt/tt	BMI at onset T2D	BMI 29 vs. 32
309 T2D	M, F, 62		Adj: nil
		BsmI, Tru9I, ApaI	T2D Adj: nil	No association
Bid et al. (364)	260	Foki, BsmI, TaqI	T2D	FFBbTt OR = 4.0 (0.6–24.7)
Indian 100 T2D	M, F, 49	Combinations	Adj: nil
Speer et al. (365)	216, M, F	BsmI	Postprandial C-peptide	↑C-peptide in T2DM and obese
29 T2D	18–83	BB vs. Bb and bb	Adj: nil
Filus et al. (366)	176, M, 52	FokI: FF/Ff vs. ff	Fasting insulin. Adj: nil	↑insulin
Polish		BsmI: BB vs. bb	BMI Adj: nil	↑BMI

Each section is listed in order of number of participants, highest to lowest. ACE, Angiotensin converting enzyme genotype; Adj, adjustments; AMM, appendicular muscle mass; ADL, activities of daily living; APOSS, Aberdeen Prospective Osteoporosis Screening Study; COPD, chronic obstructive pulmonary disease; F, female; FFM, fat-free mass; FPG, fasting plasma glucose; Ht, height; IGT, impaired glucose tolerance; M, male; N, normal group; OPUS, Osteoporosis and Ultrasound Study; OR, odds ratio; PP, postprandial; T2D, type 2 diabetes mellitus; Wt, weight.

A. FokI polymorphism

The FokI polymorphism of the VDR gene is a T/C transition in exon 2 of the VDR gene that results in a shorter 424-amino-acid protein with enhanced transactivation capacity using a reporter gene assay (184). Although this greater VDR activity might suggest improved muscle strength in light of some of the clinical data, the FokI polymorphism is associated with reduced muscle strength in two studies in men (185, 186). It is interesting to speculate that increased VDR function could increase CYP24A1 expression and thereby degradation of 1,25D.

Among 302 Caucasian men (aged 58–93 yr), those who were homozygous for the FokI polymorphism displayed significantly lower fat-free mass and appendicular muscle mass on dual-energy x-ray absorptiometry (DEXA) scanning (185). Furthermore, men with this polymorphism demonstrated a 2.17-fold higher risk of sarcopenia (defined by appendicular fat-free mass <7.26 kg/m²), independent of age. Lower fat-free mass was associated with significantly lower quadriceps muscle strength. Differences in quadriceps strength were not significant after adjusting for fat-free mass, suggesting that the difference was mediated by altered muscle mass.

In another study that included 107 patients with stable chronic obstructive pulmonary disease and 104 healthy, age-matched controls, homozygosity for the FokI polymorphism was associated with reduced quadriceps strength compared with heterozygosity or control subjects (186). The difference became more significant in a model that adjusted for age, sex, forced expiratory volume in 1 sec (FEV₁), fat-free mass, and angiotensin-converting enzyme genotypes. There was no evidence that the presence or absence of lung disease affected the relation between FokI genotype and quadriceps strength.

Among 240 women (41.5 ± 13.2 yr), those with the FokI polymorphism (FF) had weaker isometric knee extensor strength (P < 0.05 for both 90° and 120° incline) vs. those who were heterozygous (Ff) or lacking the polymorphism (ff) (187). However, on adjusting for age, height, and total fat-free mass, the differences were no longer significant, again suggesting that the polymorphism may be affecting muscle mass.

B. BsmI polymorphism

The data are less consistent for the BsmI polymorphism. This SNP is located in the 3′ region of the VDR gene, known to play an important role in the regulation of gene expression (188). In a group of 121 nonobese, healthy women over 70 yr of age, the bb genotype was associated with 23% higher quadriceps strength and 7% higher wrist strength compared with those with the BB genotype (189). However, among the 380 obese women over the age of 70 in this same study, no effect was found.

Conversely, a study of 175 young healthy women (age range 20–39 yr) in Belgium found that those with the bb genotype had lower hamstring strength on dynamometer and lower fat-free mass on DEXA compared with the BB genotype (190). The difference in hamstring strength became of borderline significance after adjustment for age, fat mass, and lean mass. Interestingly, the significance of another polymorphism known to be in linkage disequilibrium with the BsmI B allele, namely the polyadenosine repeat (ss genotype), was associated with higher hamstring strength and greater body weight and fat mass compared with those with LL genotype in this study.

Among 109 healthy female university students in China (age around 19–21 yr), those with the bb genotype of the BsmI polymorphism displayed significantly lower peak torque in concentric knee flexors at a specific setting on the isokinetic dynamometer than the combined BB and Bb group (P = 0.03) (191). However, when this parameter was tested at other settings, namely 120°/sec and 30°/sec, the differences were not statistically significant. When examining another polymorphism at the ApaI site, peak torque in eccentric knee extensors at 120°/sec was significantly lower in the AA homozygous group compared with the aa and Aa groups.

In a study of 253 men (54.9 ± 10.2 yr), Bt homozygotes (i.e. those with BB genotype at the BsmI site and tt genotype at an associated polymorphism site, namely TaqI) had higher isometric quadriceps strength at 150° on isokinetic dynamometer than b or T allele carriers without and with adjustment for confounding factors (P = 0.01 after adjustment) (187). However, no such association was found when this same parameter was tested at 90° or 120° or when assessing knee flexor strength.

Among 120 Turkish men (>65 yr), knee extensor strength on dynamometer was significantly higher in those with BB homozygosity at the BsmI site than in the Bb/bb group, but no significant association between muscle mass and strength was found (192).

Two population studies examining the rate of falls suggest that the bb genotype of the BsmI polymorphism may be protective against falls. In a study from Italy that included 259 community-dwelling older patients (>80 yr of age), the rate of falls differed according to BsmI genotype with more seen among those with BB or bb genotype on multivariate analysis (193).

Data collected from two separate population cohorts of older women, namely the Aberdeen Prospective Osteoporosis Screening Study (APOSS) and Osteoporosis and Ultrasound study (OPUS), also identified a greater incidence of self-reported recurrent falls among those with the BB genotype of the BsmI polymorphism compared with those with the bb genotype (194). Significant differences in function with greater ease in rising from a chair were seen in bb homozygotes compared with carriers of the B allele. These studies failed to demonstrate an association between Fok1 polymorphisms and balance or muscle power measurements.

Apart from VDR polymorphisms, a recent population-based study that involved 153 men and 596 women (65–101 yr) reported an association between SNP in the CYP27B1 gene (i.e. −1260 and +2838) and the risk of fracture over a 2.2-yr follow-up period (195). There was no difference in the risk of falls among subjects, and muscle strength was not examined. There are limitations in the interpretation of these data. Larger studies to assess the association between muscle strength and genetic polymorphisms are needed, and more functional studies of effects on VDR function are required.

C. VDR polymorphisms and insulin resistance/type 2 diabetes

Particular polymorphisms in the gene encoding the VDR may be associated with the development of insulin resistance and type 2 diabetes among certain populations. However, once again, the data are inconclusive due to the generally small sample size in these studies and the variability in the populations and examined endpoints. These studies have been summarized in Table 3.

VI. Vitamin D and Muscle: Human Studies

A. Myopathy

Rickets and osteomalacia have been associated with muscle weakness and hypotonia for centuries (196, 197). Weakness affecting the proximal lower limb musculature was reported in a group of adults with osteomalacia who responded to high-dose vitamin D therapy in the 1960s (198). The paper did not report whether all patients responded or whether responses were complete.

In addition to general weakness, more specific proximal muscle deficits are commonly described, including difficulty rising from a seated or squat position, ascending a flight of stairs, or lifting objects (199–201). Changes in gait, often described as waddling or penguin-like in appearance, are widely reported and are possibly a combined result of bone pain, muscle pain, and proximal weakness (199, 202). Pictures of a child with rickets demonstrates the potentially profound effects of vitamin D deficiency (Fig. 7). However, the classic pattern of proximal weakness seen in vitamin D deficiency is not specific. Many endocrine and metabolic disorders including renal failure, hyperparathyroidism, hypophosphatemia, Cushing's syndrome, and hyperthyroidism as well as glucocorticoid therapy may display similar clinical features (203, 204). Electromyographic changes seen in vitamin D-deficient subjects with muscle weakness confirm myopathy, but without specific features (201). In the reports of myopathy with vitamin D deficiency, many subjects had multiple biochemical abnormalities involving calcium, phosphate, and PTH that co-corrected with vitamin D repletion, making it difficult to assess the individual role of each component in the development of osteomalacic myopathy (205). These observations formed the basis for the belief that myopathy in these subjects was not directly related to vitamin D deficiency but rather a general result of osteomalacia and its associated biochemical abnormalities (206).

Figure 7.

Images of a child with rickets. These images of a 2-yr-old child with rickets display widening of the metaphyseal regions in the left wrist (A) and both ankles (B). The x-ray of the left wrist shows widening of the radial and ulnar metaphases with typical moth-eaten appearance of the physis and rarefaction of the metacarpal and phalangeal bones (C) with subsequent improvement after 3 months of treatment with cholecalciferol (D). These bone deformities are due to impaired mineralization of bone at a critical stage in its development. Muscle weakness, wasting, and hypotonia are also widely reported features of rickets, but their mechanism is unclear. Images are courtesy of Associate Professor Craig Munns, Childrens' Hospital Westmead, Sydney, Australia.

Figure 7.

Images of a child with rickets. These images of a 2-yr-old child with rickets display widening of the metaphyseal regions in the left wrist (A) and both ankles (B). The x-ray of the left wrist shows widening of the radial and ulnar metaphases with typical moth-eaten appearance of the physis and rarefaction of the metacarpal and phalangeal bones (C) with subsequent improvement after 3 months of treatment with cholecalciferol (D). These bone deformities are due to impaired mineralization of bone at a critical stage in its development. Muscle weakness, wasting, and hypotonia are also widely reported features of rickets, but their mechanism is unclear. Images are courtesy of Associate Professor Craig Munns, Childrens' Hospital Westmead, Sydney, Australia.

Observational and uncontrolled treatment studies

The reversibility of myopathy with vitamin D supplementation has been described in some case series (200, 207, 208). A recent series described the presence of progressive muscle weakness among young vitamin D-deficient veiled women from Saudi Arabia [90% had 25D < 8 ng/ml (20 nmol/liter)] (205). Some women required a wheelchair. Substantial improvements followed 3 months of vitamin D and calcium supplementation (800 IU and 1200 mg daily, respectively). Wheelchair-bound patients walked independently by the end of the study.

In another case series, five patients with myopathy resulting in wheelchair use were treated with vitamin D₂ (50,000 IU weekly) (209). At baseline, they were deficient [25D = 5–13 ng/ml (12–32 nmol/liter)] with secondary hyperparathyroidism (intact PTH range = 13–89 pmol/liter). Treatment resulted in marked improvements in strength, pain, and mobility within 4–6 wk, despite persisting hyperparathyroidism. The authors suggested that this indicated a role for vitamin D independent of PTH.

A study assessing vitamin D-deficient women [25D = 7 ng/ml [17 nmol/liter)] vs. controls with higher levels [25D = 19 ng/ml (47 nmol/liter)] reported an independent association between 25D levels and maximal voluntary knee extension force (208). No correlations were found for PTH or total or bone-specific alkaline phosphatase.

A common theme in these case series that describe patients with muscle pain and weakness is the high rate of initial misdiagnosis. The diagnoses of diabetic neuropathy, general debility, motor neuron disease, orthopedic disorders, psychiatric conditions, or inherited myopathy were described before the recognition of vitamin D deficiency (205, 209, 210). The nonspecific clinical features of vitamin D-deficiency myopathy, the wide range of severity from mild weakness to debilitating pain and immobility, and low index of suspicion may contribute to the frequent delay in the diagnosis.

We are not aware of any reports of muscle biopsy or muscle function studies in people with mutations in VDR.

B. Myalgia and vitamin D deficiency

People with vitamin D deficiency and proximal myopathy (i.e. weakness of the proximal musculature arising from muscle pathology) often have associated proximal myalgia (i.e. muscle pain) (198). Many authors have also proposed that low vitamin D is associated with more diffuse muscle pain (211–213). However, this is controversial, and other studies do not support this (214–216). The issue is made more difficult because osteomalacia is associated with bone pain and microfractures, making causal discrimination of the source of pain challenging. Because it is conceptually obvious that people with muscle pain may be less likely to exercise, go out, and carry out normal outside activities of daily living, establishing cause and effect is important. Ideally, demonstrating a therapeutic response would clarify the issue.

1. Observational studies

A cross-sectional study of 3075 men from eight European centers found that those who reported chronic widespread pain (8.6%) were more likely to have low 25D levels [<15 ng/ml (37.5 nmol/liter]) (217). However, the relationship was attenuated by adjusting for age, season, activity, and other factors.

Ninety-three percent of 153 patients who were being assessed for persistent, nonspecific musculoskeletal pain in Minneapolis were vitamin D deficient [mean 25D = 12 ng/ml [30 nmol/liter)] (211). All African-American, East African, Hispanic, and American Indian patients had 25D below 20 ng/ml (<50 nmol/liter) as did 82% of Caucasian patients. None had fibromyalgia or medical conditions known to decrease production, absorption, or hydroxylation of vitamin D. This study did not include a control group of similar ethnicity.

The propensity for particular ethnic groups, including those migrating from Asia and the Indian subcontinent to Western countries, to develop myalgia and bone pain as the primary manifestation of vitamin D deficiency has been reported since the 1970s (218, 219). A study describing 33 mostly Somalian female asylum seekers with musculoskeletal pain and low 25D [<8.5 ng/ml [21 nmol/liter)] found that vitamin D and calcium supplementation led to the symptom resolution in 22 (66.7%) by 3 months (220). The authors noted a 2.5-yr mean lag time between symptom onset and diagnosis. There was no control group. A study from the United Arab Emirates found that 86% of patients who were initially diagnosed with fibromyalgia or nonspecific muscle pain were vitamin D deficient. The majority reported improvement in response to supplementation (221). Another study compared cultural differences in the reporting of muscle pain among South Asians (i.e. Indian, Pakistani, and Bangladeshi) and white Europeans living in England (212). Reporting of widespread pain was significantly more common in the 1945 South Asians. However, in the 137 South Asians in whom 25D was measured, there was no association between deficiency and pain.

A report describing myalgia in six women who had migrated to the Netherlands considered vitamin D deficiency [<8 ng/ml (<20 nmol/liter) in 5 patients] to be the cause. There was a lengthy lag period (7–103 months) from the onset of symptoms to diagnosis (222). In three cases, misdiagnosis led to treatment with prednisone, estrogen, or cholecystectomy. Vitamin D and calcium supplementation was effective in reversing the myalgia in each case.

2. Case-control studies

Muscle pain was recently proposed as a marker for vitamin D deficiency among Aboriginal Australians (223). A case-control study of eight urban Aboriginal patients with muscle pain and eight matched Aboriginal controls without pain reported significantly lower vitamin D levels among those with pain [17 vs. 23 ng/ml (41 vs. 58 nmol/liter), P = 0.017].

Wide cultural and gender differences in the reporting of pain, subjective features in the diagnosis of fibromyalgia, and the presence of other features known to affect vitamin D status among patients with persistent pain syndromes confound the assessment of the role of vitamin D deficiency in muscle pain. Also, the observational nature of these studies does not equip them to address the question of causality.

3. Randomized controlled trials (RCT) for myalgia

We identified only one randomized placebo-controlled trial of supplementation where treatment of muscle pain appeared to be the primary endpoint. The study examined people with diffuse muscle pain (214). Fifty subjects with 25D below 20 ng/ml (50 nmol/liter) at baseline were randomized to placebo or vitamin D₂ 50,000 IU weekly for 3 months. There was no benefit of treatment. The authors note that 50% of the placebo group achieved normal vitamin D levels during the study; however, the improvement in pain scores was not substantial for either group. Using the PowerStat program (224), we calculate that the study had 80% power with α of 0.05 to detect a difference of ±19 in pain score. The baseline visual analog pain score in the treatment group was high at 67 ± 23, so if there is any benefit, it is probably smaller than this.

4. Summary: myalgia

Vitamin D deficiency with osteomalacia is associated with muscle pain that in most cases resolves with treatment. The pain is more commonly located in large proximal muscle groups rather than displaying diffuse distribution (198, 222, 225, 226) and is often associated with bone pain and other features of osteomalacia and myopathy (205, 208).

Thus, for pain (proximal or diffuse) in patients without osteomalacia, other etiologies should also be considered. In patients with diffuse pain, without obvious osteomalacia, the data remain inconclusive. There are strong associations, but the only RCT found no convincing benefit of supplementation. The trial was adequately powered to detect a clinically meaningful change in pain score.

There are no RCT examining specific treatment of proximal muscle pain. Larger randomized placebo-controlled trials should be carried out, preferably with stratification by baseline vitamin D status, in people with fibromyalgia and in people with proximal myalgia. There is no evidence to support supplementation for myalgia in people with normal levels.

C. Fibromyalgia

Fibromyalgia is not purely a muscle disorder, but there are a number of studies examining the potential association between it and vitamin D. Myalgia was examined in a cross-sectional study of 6824 white, middle-aged subjects living in the United Kingdom. A significant association between fibromyalgia, defined by the American College of Rheumatology criteria, and 25D was found among women (227). However, no such association was found in men, although they reported similar rates of pain (11.4% for men, 12.5% for women). No association with myalgia was found.

In two separate case-control studies of patients with fibromyalgia from the United States and Brazil, no statistically significant differences were found in 25D levels (214, 228).

In contrast, another case-control study that examined 40 premenopausal women with fibromyalgia and 37 controls found a significantly higher proportion of vitamin D deficiency [25D < 8 ng/ml (20 nmol/liter)] among women with fibromyalgia (229). However, this was not adjusted for physical activity, smoking, or body mass index (BMI). Fibromyalgia symptoms did not differ depending on the vitamin D status. A subset of deficient patients who received supplementation (eight of 18) reported subjective improvement that persisted at 3 months; however, 10 of 18 did not.

One placebo-controlled study examining the effect of vitamin D on fibromyalgia was identified (230). In that study of 138 patients with fibromyalgia, the subset of 100 patients with mild to moderate vitamin D deficiency and insufficiency [25D = 10–25 ng/ml (25–62.5 nmol/liter)] who were randomized to receive vitamin D₃ (50,000 IU weekly) showed significant improvement over 8 wk vs. placebo-treated controls. However, this did not persist at 1 yr, and in the same study, the subset of 38 people with severe deficiency [25D <10 ng/ml (25 nmol/liter)] who received vitamin D in an unblinded fashion did not report any improvement at either 8 wk or 1 yr (230).

Overall, there is conflicting evidence regarding the possibility of an association between low vitamin D and fibromyalgia, and clearly, having fibromyalgia may have an impact on time spent outdoors/exercising. The data from the one randomized placebo-controlled trial do not provide a clear answer, because the most deficient subjects did not benefit, but less deficient subjects did. More research is needed in this area.

D. Drug-related myopathy and vitamin D

1. Aromatase inhibitors

The effect of vitamin D supplementation on myalgia due to a drug class, namely aromatase inhibitors, has been recently reported. For this class, there is both observational and randomized controlled data, and myalgia is a very common side effect.

An observational study found significantly less musculoskeletal pain among 60 women on letrozole who had achieved median 25D levels over 66 ng/ml (165 nmol/liter) compared with women with levels below 66 ng/ml (165 nmol/liter) (19 vs. 52%) after weekly supplementation with 50,000 IU vitamin D₃ for 12 wk (231).

In a double-blind RCT, 60 patients with early-stage breast cancer with new or worsening musculoskeletal pain on aromatase inhibitor therapy were randomized to receive either high-dose vitamin D supplementation at a regimen that depended on their baseline 25D or placebo (232). Those with 25D of 10–19 ng/ml (25–47 nmol/liter) received 50,000 IU vitamin D₂ for 16 wk, whereas those with 25D of 20–29 ng/ml (50–72 nmol/liter) received 50,000 IU for 8 wk (232). There were significant improvements in pain at 2 months in the vitamin D group vs. placebo on the basis of several indices. Therapy was decreased from weekly to monthly after 2 months in most subjects. The beneficial effects did not remain at the 4- and 6-month visits. There was evidence of a dose-response effect; women who were more deficient had greater benefits, and in that subgroup, the beneficial effect was seen across the whole study period.

2. 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins)

A number of reports suggest that vitamin D deficiency may potentiate myopathy in patients on lipid-lowering statin therapy (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors) (233–242). These reports are both anecdotal and based on case series and cross-sectional studies. Not all studies have confirmed this relationship (237).

Cross-sectional and cohort studies.

Among a group of 621 statin-treated patients, the 128 who reported myalgia had lower serum 25D (238). Levels were low [defined as <32 ng/ml (<80 nmol/liter) in that study] in 64% of myalgic patients vs. 43% of the others. A subset of 38 of the 82 25D-deficient myalgic patients were treated with 50,000 IU/wk of vitamin D₂ for 12 wk (unblinded) while continuing statins, and 35 had their myalgia resolve. The three nonresponders achieved similar vitamin D levels.

A prospective study of 150 statin-intolerant patients with 25D below 32 ng/ml (80 nmol/liter) reported that 83% were free of myalgia and no longer statin intolerant after approximately 8 months of vitamin D₂ treatment (50,000 IU twice weekly for 3 wk and then 50,000 IU weekly) (240). However, treatment had little effect on elevated creatine phosphokinase (CPK).

However, not all studies find an association. A retrospective study of 6808 statin users found no correlation between 25D levels, myalgia, or CPK levels (242). A smaller study of 129 patients on statins also found no difference in the 25D levels of those with and without myalgia (237).

Some hypotheses have been proposed regarding mechanisms by which vitamin D deficiency may potentiate statin-induced myalgia. The suggestion that statins may reduce vitamin D synthesis by inhibition of synthesis of its cholesterol precursor has not been supported by clinical studies (243, 244). The enzyme CYP34 demonstrates in vitro 25-hydroxylase activity (245), and it has been speculated that vitamin D deficiency may lead to preferential shunting or use of this enzyme for vitamin D hydroxylation, reducing its availability to metabolize (deactivate) statins (239). This hypothesis could be tested by measuring statin levels in vitamin D-deficient and vitamin D-sufficient individuals matched for the presence or absence of myopathy and/or CPK levels.

Although an association between a polymorphism of the solute carrier organic anion transporter family member 1B1 gene (SLCO1B1) and statin-induced myalgia was reported, no interaction between vitamin D deficiency and genotype was found in a group of 46 patients on statin therapy (241).

These studies of statin myalgia/myopathy are interesting; however, their unblinded nature and lack of control groups are particular limitations, especially given the well-known placebo effect in pain studies. At this time, the evidence of an association between vitamin D deficiency and statin-related myalgia is derived from observational studies and small series. Obviously, people who experience pain with muscle movement may be less likely to be participating in outdoor activities and may therefore make less vitamin D than their pain-free counterparts. Randomized placebo-controlled studies are needed. In the meantime, we suggest treating deficient patients because of the known bone and calcium benefits. There is at present no evidence to support treating people on statins who have normal vitamin D status.

3. Summary: drug-related myopathy and vitamin D

Myalgia has been observed in patients receiving statins or aromatase inhibitors. A number of these studies reveal that patients on statins who suffer from myalgia are also vitamin D deficient, and vitamin D supplementation might improve symptoms of myalgia in these patients. These findings suggest that vitamin D deficiency may potentiate statin-induced myalgia, but the molecular mechanisms underlying the interaction between vitamin D, statin treatment, and muscle function have not been elucidated. Based on the limited data, we recommend treating all deficient subjects who are receiving statins or aromatase inhibitors. The only RCT in patients taking aromatase inhibitor used high-dose therapy. If this is used, patients should be monitored for hypercalcemia and hypercalciuria.

E. Falls and vitamin D

Approximately 30% of community-dwelling people over the age of 65 fall each year, and approximately 20% of these require medical attention (246). Falls pose a substantial risk to an aging population, are a major risk factor for fracture and other injury, and impact negatively on quality of life (247). Therefore, identifying reversible factors is important. In older individuals, falls are closely related to sarcopenia (loss of muscle mass), loss of muscle tone, and a range of conditions that contribute to the complex syndrome of frailty (248). This issue has also recently been discussed in an Endocrine Society statement on extraskeletal roles of vitamin D (12).

1. Falls: observational studies

There is a seasonal variation in the incidence of falls, with more occurring in winter among older women. This raises the suggestion of a putative role for vitamin D in the occurrence of falls (249), although other factors such as decreased daylight and increased likelihood of slipping on wet or icy surfaces could also explain the differences. The possibility that vitamin D deficiency, which is highly prevalent in frail and older individuals, may contribute to falls has been examined by a number of studies. These are summarized in Table 4.

Table 4.

Observational studies assessing the longitudinal effect of vitamin D levels on falls/muscle function (listed in order of number of study participants, highest to lowest)

Study (Ref.) N, Sex, Age, Duration, Predictors	Outcomes	Main results	Risk	Adjustments
Faulkner et al. (367)   9526, F, 70   4 yr vitamin D supplement	Quadriceps & grip strength, walk speed, falls, others	No associations	IRR = 0.70,	Age, clinic, season, Ht, ETOH, activity, BMI, education, ethnicity, smoking, creatinine, comorb, drugs, Ca.
Faulkner et al. (367)   389, F, 70   4 yr, basal 25D, 1,25D, PTH		↑ 1,25D (40–80 vs. 7–26 pg/ml), ↓falls ↑ 25D associated with ↓ grip strength
Flicker et al. (250)   1619, F, 84, assisted care   145–168 d, basal 25D	Falls: staff-reported	↑ log[25D] ↓ falls	HR = 0.74 (0.59–0.94)	Wt, cognition, drugs, past Colles fracture, wandering behavior
Snidjer et al. (251)	Falls: self-reported	25D <10 ng/ml ↑ risk ≥2 falls	OR = 1.78	Age, sex, ETOH, region, season, activity, education, smoking
1231, M, F, >65			(1.06–2.99)
1 yr		25D <10 ng/ml ↑ risk ≥3 falls	OR = 2.23
Basal 25D			(1.17–4.25)
Visser et al. (280)   1008, M, F, >65   3 yr, basal 25D	Grip strength ASMM (DEXA)	25HD <10 ng/ml vs. >20 greater risk of a decline	OR = 2.57 (1.4–4.7)	Activity, BMI, season, creatinine, smoking, comorb
Visser et al. (280)   331, M,F, >65   3 yr, basal 25D		25HD <10 vs. >20 ng/ml greater risk of sarcopenia	OR = 2.17 (0.73–6.33)
Wicherts et al. (279)   939, M, F, >65   3 yr,   Basal 25D	Score: TCST, tandem stand, walking	25D <10 ng/ml ↑ risk of ↓ in score 25D 10–20 ng/ml ↑ risk of ↓ in score	OR = 2.21 (1.0–4.87) OR = 2.01 (1.06–3.81)	Age, sex, co-morb, ETOH, BMI, urbanization
Dam et al. (281)   769, M, F, 75   2.5 yr   Basal 25D	TUAG, TCST, grip strength	♀ 25D <32 vs. >115 ng/ml ↑ decline in TUAG, TCST ♂ 25D <36 vs. >49 ng/ml poorer grip	20 vs. 8% decline 32.1 vs. 34.1 kg	Age, sex, BMI, activity, ETOH, estrogen use
Chan (282)   714, M, >65   4 yr   Basal 25D	ASMM, grip, walk speed, others	No associations		Age, BMI, ETOH, comorb, smoking, diet, activity, season, PTH
Verreault et al. (368)	Strength (hip, knee, grip), walking speed and TCST	No associations		Age, race, BMI, education, baseline scores, comorb   628, M, F, >65   3 yr   Basal 25D

Study (Ref.) N, Sex, Age, Duration, Predictors	Outcomes	Main results	Risk	Adjustments
Faulkner et al. (367)   9526, F, 70   4 yr vitamin D supplement	Quadriceps & grip strength, walk speed, falls, others	No associations	IRR = 0.70,	Age, clinic, season, Ht, ETOH, activity, BMI, education, ethnicity, smoking, creatinine, comorb, drugs, Ca.
Faulkner et al. (367)   389, F, 70   4 yr, basal 25D, 1,25D, PTH		↑ 1,25D (40–80 vs. 7–26 pg/ml), ↓falls ↑ 25D associated with ↓ grip strength
Flicker et al. (250)   1619, F, 84, assisted care   145–168 d, basal 25D	Falls: staff-reported	↑ log[25D] ↓ falls	HR = 0.74 (0.59–0.94)	Wt, cognition, drugs, past Colles fracture, wandering behavior
Snidjer et al. (251)	Falls: self-reported	25D <10 ng/ml ↑ risk ≥2 falls	OR = 1.78	Age, sex, ETOH, region, season, activity, education, smoking
1231, M, F, >65			(1.06–2.99)
1 yr		25D <10 ng/ml ↑ risk ≥3 falls	OR = 2.23
Basal 25D			(1.17–4.25)
Visser et al. (280)   1008, M, F, >65   3 yr, basal 25D	Grip strength ASMM (DEXA)	25HD <10 ng/ml vs. >20 greater risk of a decline	OR = 2.57 (1.4–4.7)	Activity, BMI, season, creatinine, smoking, comorb
Visser et al. (280)   331, M,F, >65   3 yr, basal 25D		25HD <10 vs. >20 ng/ml greater risk of sarcopenia	OR = 2.17 (0.73–6.33)
Wicherts et al. (279)   939, M, F, >65   3 yr,   Basal 25D	Score: TCST, tandem stand, walking	25D <10 ng/ml ↑ risk of ↓ in score 25D 10–20 ng/ml ↑ risk of ↓ in score	OR = 2.21 (1.0–4.87) OR = 2.01 (1.06–3.81)	Age, sex, co-morb, ETOH, BMI, urbanization
Dam et al. (281)   769, M, F, 75   2.5 yr   Basal 25D	TUAG, TCST, grip strength	♀ 25D <32 vs. >115 ng/ml ↑ decline in TUAG, TCST ♂ 25D <36 vs. >49 ng/ml poorer grip	20 vs. 8% decline 32.1 vs. 34.1 kg	Age, sex, BMI, activity, ETOH, estrogen use
Chan (282)   714, M, >65   4 yr   Basal 25D	ASMM, grip, walk speed, others	No associations		Age, BMI, ETOH, comorb, smoking, diet, activity, season, PTH
Verreault et al. (368)	Strength (hip, knee, grip), walking speed and TCST	No associations		Age, race, BMI, education, baseline scores, comorb   628, M, F, >65   3 yr   Basal 25D

ASMM, Appendicular skeletal muscle mass; Ca, calcium intake; comorb, comorbid conditions; ETOH, alcohol intake; HR, hazard ratio; Ht, height; IRR, incidence rate ratio; OR, odds ratio; TCST, timed chair stand tests; Wt, weight.

Table 4.

Observational studies assessing the longitudinal effect of vitamin D levels on falls/muscle function (listed in order of number of study participants, highest to lowest)

Study (Ref.) N, Sex, Age, Duration, Predictors	Outcomes	Main results	Risk	Adjustments
Faulkner et al. (367)   9526, F, 70   4 yr vitamin D supplement	Quadriceps & grip strength, walk speed, falls, others	No associations	IRR = 0.70,	Age, clinic, season, Ht, ETOH, activity, BMI, education, ethnicity, smoking, creatinine, comorb, drugs, Ca.
Faulkner et al. (367)   389, F, 70   4 yr, basal 25D, 1,25D, PTH		↑ 1,25D (40–80 vs. 7–26 pg/ml), ↓falls ↑ 25D associated with ↓ grip strength
Flicker et al. (250)   1619, F, 84, assisted care   145–168 d, basal 25D	Falls: staff-reported	↑ log[25D] ↓ falls	HR = 0.74 (0.59–0.94)	Wt, cognition, drugs, past Colles fracture, wandering behavior
Snidjer et al. (251)	Falls: self-reported	25D <10 ng/ml ↑ risk ≥2 falls	OR = 1.78	Age, sex, ETOH, region, season, activity, education, smoking
1231, M, F, >65			(1.06–2.99)
1 yr		25D <10 ng/ml ↑ risk ≥3 falls	OR = 2.23
Basal 25D			(1.17–4.25)
Visser et al. (280)   1008, M, F, >65   3 yr, basal 25D	Grip strength ASMM (DEXA)	25HD <10 ng/ml vs. >20 greater risk of a decline	OR = 2.57 (1.4–4.7)	Activity, BMI, season, creatinine, smoking, comorb
Visser et al. (280)   331, M,F, >65   3 yr, basal 25D		25HD <10 vs. >20 ng/ml greater risk of sarcopenia	OR = 2.17 (0.73–6.33)
Wicherts et al. (279)   939, M, F, >65   3 yr,   Basal 25D	Score: TCST, tandem stand, walking	25D <10 ng/ml ↑ risk of ↓ in score 25D 10–20 ng/ml ↑ risk of ↓ in score	OR = 2.21 (1.0–4.87) OR = 2.01 (1.06–3.81)	Age, sex, co-morb, ETOH, BMI, urbanization
Dam et al. (281)   769, M, F, 75   2.5 yr   Basal 25D	TUAG, TCST, grip strength	♀ 25D <32 vs. >115 ng/ml ↑ decline in TUAG, TCST ♂ 25D <36 vs. >49 ng/ml poorer grip	20 vs. 8% decline 32.1 vs. 34.1 kg	Age, sex, BMI, activity, ETOH, estrogen use
Chan (282)   714, M, >65   4 yr   Basal 25D	ASMM, grip, walk speed, others	No associations		Age, BMI, ETOH, comorb, smoking, diet, activity, season, PTH
Verreault et al. (368)	Strength (hip, knee, grip), walking speed and TCST	No associations		Age, race, BMI, education, baseline scores, comorb   628, M, F, >65   3 yr   Basal 25D

Study (Ref.) N, Sex, Age, Duration, Predictors	Outcomes	Main results	Risk	Adjustments
Faulkner et al. (367)   9526, F, 70   4 yr vitamin D supplement	Quadriceps & grip strength, walk speed, falls, others	No associations	IRR = 0.70,	Age, clinic, season, Ht, ETOH, activity, BMI, education, ethnicity, smoking, creatinine, comorb, drugs, Ca.
Faulkner et al. (367)   389, F, 70   4 yr, basal 25D, 1,25D, PTH		↑ 1,25D (40–80 vs. 7–26 pg/ml), ↓falls ↑ 25D associated with ↓ grip strength
Flicker et al. (250)   1619, F, 84, assisted care   145–168 d, basal 25D	Falls: staff-reported	↑ log[25D] ↓ falls	HR = 0.74 (0.59–0.94)	Wt, cognition, drugs, past Colles fracture, wandering behavior
Snidjer et al. (251)	Falls: self-reported	25D <10 ng/ml ↑ risk ≥2 falls	OR = 1.78	Age, sex, ETOH, region, season, activity, education, smoking
1231, M, F, >65			(1.06–2.99)
1 yr		25D <10 ng/ml ↑ risk ≥3 falls	OR = 2.23
Basal 25D			(1.17–4.25)
Visser et al. (280)   1008, M, F, >65   3 yr, basal 25D	Grip strength ASMM (DEXA)	25HD <10 ng/ml vs. >20 greater risk of a decline	OR = 2.57 (1.4–4.7)	Activity, BMI, season, creatinine, smoking, comorb
Visser et al. (280)   331, M,F, >65   3 yr, basal 25D		25HD <10 vs. >20 ng/ml greater risk of sarcopenia	OR = 2.17 (0.73–6.33)
Wicherts et al. (279)   939, M, F, >65   3 yr,   Basal 25D	Score: TCST, tandem stand, walking	25D <10 ng/ml ↑ risk of ↓ in score 25D 10–20 ng/ml ↑ risk of ↓ in score	OR = 2.21 (1.0–4.87) OR = 2.01 (1.06–3.81)	Age, sex, co-morb, ETOH, BMI, urbanization
Dam et al. (281)   769, M, F, 75   2.5 yr   Basal 25D	TUAG, TCST, grip strength	♀ 25D <32 vs. >115 ng/ml ↑ decline in TUAG, TCST ♂ 25D <36 vs. >49 ng/ml poorer grip	20 vs. 8% decline 32.1 vs. 34.1 kg	Age, sex, BMI, activity, ETOH, estrogen use
Chan (282)   714, M, >65   4 yr   Basal 25D	ASMM, grip, walk speed, others	No associations		Age, BMI, ETOH, comorb, smoking, diet, activity, season, PTH
Verreault et al. (368)	Strength (hip, knee, grip), walking speed and TCST	No associations		Age, race, BMI, education, baseline scores, comorb   628, M, F, >65   3 yr   Basal 25D

ASMM, Appendicular skeletal muscle mass; Ca, calcium intake; comorb, comorbid conditions; ETOH, alcohol intake; HR, hazard ratio; Ht, height; IRR, incidence rate ratio; OR, odds ratio; TCST, timed chair stand tests; Wt, weight.

In 1619 women in low-level and high-level residential care (mean age 84 yr), a significant inverse association between serum 25D levels and the incidence of falls over approximately 5 months was reported. The authors estimated a 20% reduction in falls risk with doubling vitamin D status on analysis of log[25D] levels (250). A similar-sized study of 1231 community-dwelling individuals identified baseline 25D as a predictor for falls over a 1-yr period, particularly among those 65–75 yr of age (251). Those with 25D levels over 10 ng/ml (25 nmol/liter) displayed the highest risk of recurrent falls.

However, in a smaller study, although older individuals who fell had significantly lower 25D levels vs. the overall group of 83 subjects, this was not significant on multivariate analysis (252).

The possibility that 25D does not directly contribute to falls but is rather an associative marker of frailty remains a potential limitation in the interpretation of these observational data. As in the situation with myalgia, it is obvious that people who fall may spend less time outdoors and thereby have lower exposure to solar UV radiation. The other issue is that malnutrition is very common in elderly persons, affecting up to 40% of those living in institutions, and may contribute simultaneously to vitamin D deficiency and frailty.

2. Falls: interventional studies

Interventional studies seeking to examine the effects of vitamin D supplementation or UV exposure on the risk of falls among older individuals have been performed and are summarized in Table 5.

Table 5.

Interventional studies assessing the effects of vitamin D supplementation on the incidence of falls (listed in order of number of study participants, highest to lowest)

Study (Ref.), Positive vs. Negative, Duration, Basal 25D, Other	n, Sex, Age	Vitamin D (IU), Ca (mg)	Outcome Proven ↑25D, Adjustments	Main Results, RR/OR/HR/IRR/NNT where given
Larsen et al. (254)	9605	D3 400 + Ca 1000 vs. home visit vs. nil	Severe falls, not proven	12% decrease
Positive 3 yr NR	F >66		Adj: age, marital status, intervention	RR = 0.88; (0.79–0.98) NNT 9
Arden et al. (369)	6641	D2 im, 300,000/yr vs. placebo	Falls, fracture, knee pain	No change
Negative 3 yr	M, F		Not proven
NR	>75		Adj: treatment
Grant et al. (265)	5292	D3 + Ca 1000 vs.	Fracture, falls	No change
Negative 24–62 months	M, F	D3 800 vs.	↑ Proven	HR = 0.97
15 ng/ml (n = 16) Post fracture	>70	placebo	Adj: minimization variables
Law et al. (370)	3717	D2 100,000/3 months vs. placebo	Fracture, falls; ↑ proven	No change
Negative 10 months	M, F		Adj: age, sex, time in the trial, cluster	RR = 1.09
19 ng/ml (47) (n = 16). Inst	85
Porthouse et al. (266)   Negative 25 months   NR. Inst	3314 M, F >70	D3 800 + Ca 1000 + leaflet vs. leaflet	Fracture, falls, QOL Not proven Adj: practice	No change
Chapuy et al. (371)   Positive 18 months   13–16 ng/ml. Inst	3270 M, F 84	D3 800 + Ca 1200 vs. Ca alone	Fracture, 25OHD, PTH Yes Adj:nil	99% fracture from a fall ↓ fracture. Falls risk NR
Sanders et al. (267)	2256	D3 500,000/yr vs. placebo	Fracture, falls; ↑ proven	Higher falls and fracture
Adverse 4–6 yr   20 (49)	F >70		Adj: nil	RR = 1.15 (1.02–1.30) RR fracture = 1.26 (1.0–1.59)
Glendenning et al. (290)	686	D3 150,000 /3m vs. placebo	Falls, TUAG, grip	No changes
Negative 9 months	F		↑ Proven	OR = 1.06
26 ng/ml (n = 40)	77		Adj: age, falls, follow-up
Flicker et al. (255)   Positive, post hoc subgroup. 2 yr   <24 (89%). Inst	625 M, F 83	D2 10,000/wk + Ca 600 then D2 1,000/d + Ca vs. Ca alone	Fracture, falls Not proven Adj: Wt, cognition, drugs, level of care, wandering	Compliant ↓ falls risk IRR = 0.63 (0.48–0.82)
Sambrook et al. (253)   Positive, post hoc subgroup. 12 m   13 ng/ml. NH	602 M, F >70	Extra 30–40 min/d sunlight + Ca 600 vs. nil	Change in 25OHD and falls Not proven Adj: age, sex, falls, balance, comorb, cognition, incontinence, care level	Compliant ↓falls risk IRR = 0.52 (0.31–0.88)
Chapuy et al. (372)	583	D3 800 + Ca 1200 vs.	Fracture, 25OHD, PTH	No change
Negative 2 yr	F	D3 800 vs. placebo vs. Ca alone	↑ Proven
<20 (79%). Inst	85		Adj: nil
Gallagher et al. (373)	489	1,25D 0.5 μg/d vs. placebo ± E/P	Falls	↓ falls. CrCl < or >60
Positive 3 yr	F		Not proven	RR = 0.47 (0.29–0.78)
31–33 ng/ml	66–77		Adj: age, Wt, Ht, drugs, basal 25D and Ca absorption, comorb, smoking	RR = 0.70 (0.51–0.96)
Bischoff-Ferrari et al. (256).   Positive, women only.   3 yr   27–33 ng/ml	445 M, F >65	D3 700 + Ca 500 vs. Ca alone	Falls (self-report); ↑ proven Adj: age, sex, BMI, Ca intake, CrCl, comorb, basal 25D and PTH, activity, ETOH, smoking	↓ falls, women only OR = 0.54 (0.30–0.97)
Dawson-Hughes et al. (257)   Positive fracture, adverse falls ♀. 3 yr   27–33 ng/ml	389 M, F >65	D3 700 + Ca 500 vs. Ca alone	Fracture, falls (self-report), BMD ↑ Proven Adj: nil	↑ falls in women ↓ fracture (nonvertebral) Falls data not shown
Dukas et al. (374)   Positive, post hoc subgroup. 36 wk   28–30 ng/ml	378 M, F >70	1 μg 1α−OHD3 daily vs. placebo	Falls Not proven Adj: age, BMI, sex falls, activity, CCMI, drugs, heart rate, Ca intake, biochemistry	Ca intake >512 mg/d ↓ fallers OR = 0.46 (0.22–0.99) CrCl < 65, ↓falls OR = 0.29 (0.09–0.88)
Graafmans et al. (263)	354	D3 400 vs. placebo	Falls (self-reported)	No change
Negative. 28 wk	M, F		Not proven	OR = 1
NR. NH	>70		Adj: nil
Prince et al. (260)	302	D2 1000 + Ca 1000 vs. Ca alone	Falls (self-report)	Cal ± D ↓ risk
Positive 1 yr	F 70–90		↑ Proven	OR = 0.61 (0.37–0.99)
<24 ng/ml			Adj: Ht
Pfeifer et al. (258)   Positive. 12 + 8 months   <31 ng/ml	242 M, F 77	D3 800 + Ca 1000 vs. Ca alone	Falls, quad strength, sway, TUAG ↑ Proven Adj: nil	↓ falls RR = 0.73 (0.54–0.96) ↑strength, ↓sway, ↓TUAG
Burleigh et al. (375)	205	D3 800 + Ca 1200 vs. Ca alone	Falls (staff report)	No change
Negative 30 d	M, F		Not proven	RR = 0.82
8.8. ng/ml AGU	84		Adj: nil
Berggren et al. (376)   Trend 1 yr   NR. fracture NOF	199 M, F 82	D3 800 + Ca 1000 + falls prevention vs. normal care	Falls Not proven Adj: dementia and depression	Trend to ↓ falls, P = 0.063 IRR = 0.64 (0.40–1.02)
Harwood et al. (377)   Positive 1 yr   ∼12 ng/ml. fracture hip	150 F 81	D2 300,000 im + Ca 1000 vs. D3 800 + Ca vs. Ca	Falls, 25D, PTH ↑ Proven Adj: age, fracture, BMD, biochemistry, prefracture mobility	↓ falls 0.48 (0.26–0.90)
Pfeifer et al. (262)   Positive 1 yr   <20 ng/ml	148 F 74	D3 800 + Ca 1200 vs. Ca alone	Falls, body sway ↑ Proven Adj: nil	↓ falls in calcium + D group 0.24 vs. 0.45. ↓ sway
Broe et al. (264)	124	D2 200, 400, 600, or 800 or placebo	Falls (staff report)	800 IU ↓ falls vs. all others
Positive, post hoc subgroup. 5 months	M, F 89		↑ Only in the 800 group Adj: age, multivitamin use	IRR = 0.28 (0.11–0.75)
19.5 ng/ml NH
Bischoff et al. (259)   Positive 6w + 12 wk   <31 ng/ml. Inst	122 F 85	D3 800 + Ca 1200 vs. Ca alone	Falls, TUAG, knee + grip strength ↑ Proven Adj: age, falls, basal 1,25D and 25D, observation time	↓ falls, muscle function improved OR = 49% (14–71%)
Sato et al. (85)	96	D2 1000 vs. placebo	Falls, strength, biopsy	↓ falls, increased type II fibers
Positive 8 w + 2 yr	F		↑ Proven	RR = 0.6 (0.4–0.8)
<10 ng/ml	74		Adj: falls, age, Ht, Wt, BMI, strength, basal 25D, 1,25D, PTH, biopsy, walking aid
Sato et al. (378) Positive fracture Negative falls. 18 months 11 ng/ml	96 M, F 71	1 μg 1α−OHD3 vs. placebo	Fracture, falls, BMD, PTH Only 1,25D Adj: nil	↓ nonvertebral fracture, falls no change

Study (Ref.), Positive vs. Negative, Duration, Basal 25D, Other	n, Sex, Age	Vitamin D (IU), Ca (mg)	Outcome Proven ↑25D, Adjustments	Main Results, RR/OR/HR/IRR/NNT where given
Larsen et al. (254)	9605	D3 400 + Ca 1000 vs. home visit vs. nil	Severe falls, not proven	12% decrease
Positive 3 yr NR	F >66		Adj: age, marital status, intervention	RR = 0.88; (0.79–0.98) NNT 9
Arden et al. (369)	6641	D2 im, 300,000/yr vs. placebo	Falls, fracture, knee pain	No change
Negative 3 yr	M, F		Not proven
NR	>75		Adj: treatment
Grant et al. (265)	5292	D3 + Ca 1000 vs.	Fracture, falls	No change
Negative 24–62 months	M, F	D3 800 vs.	↑ Proven	HR = 0.97
15 ng/ml (n = 16) Post fracture	>70	placebo	Adj: minimization variables
Law et al. (370)	3717	D2 100,000/3 months vs. placebo	Fracture, falls; ↑ proven	No change
Negative 10 months	M, F		Adj: age, sex, time in the trial, cluster	RR = 1.09
19 ng/ml (47) (n = 16). Inst	85
Porthouse et al. (266)   Negative 25 months   NR. Inst	3314 M, F >70	D3 800 + Ca 1000 + leaflet vs. leaflet	Fracture, falls, QOL Not proven Adj: practice	No change
Chapuy et al. (371)   Positive 18 months   13–16 ng/ml. Inst	3270 M, F 84	D3 800 + Ca 1200 vs. Ca alone	Fracture, 25OHD, PTH Yes Adj:nil	99% fracture from a fall ↓ fracture. Falls risk NR
Sanders et al. (267)	2256	D3 500,000/yr vs. placebo	Fracture, falls; ↑ proven	Higher falls and fracture
Adverse 4–6 yr   20 (49)	F >70		Adj: nil	RR = 1.15 (1.02–1.30) RR fracture = 1.26 (1.0–1.59)
Glendenning et al. (290)	686	D3 150,000 /3m vs. placebo	Falls, TUAG, grip	No changes
Negative 9 months	F		↑ Proven	OR = 1.06
26 ng/ml (n = 40)	77		Adj: age, falls, follow-up
Flicker et al. (255)   Positive, post hoc subgroup. 2 yr   <24 (89%). Inst	625 M, F 83	D2 10,000/wk + Ca 600 then D2 1,000/d + Ca vs. Ca alone	Fracture, falls Not proven Adj: Wt, cognition, drugs, level of care, wandering	Compliant ↓ falls risk IRR = 0.63 (0.48–0.82)
Sambrook et al. (253)   Positive, post hoc subgroup. 12 m   13 ng/ml. NH	602 M, F >70	Extra 30–40 min/d sunlight + Ca 600 vs. nil	Change in 25OHD and falls Not proven Adj: age, sex, falls, balance, comorb, cognition, incontinence, care level	Compliant ↓falls risk IRR = 0.52 (0.31–0.88)
Chapuy et al. (372)	583	D3 800 + Ca 1200 vs.	Fracture, 25OHD, PTH	No change
Negative 2 yr	F	D3 800 vs. placebo vs. Ca alone	↑ Proven
<20 (79%). Inst	85		Adj: nil
Gallagher et al. (373)	489	1,25D 0.5 μg/d vs. placebo ± E/P	Falls	↓ falls. CrCl < or >60
Positive 3 yr	F		Not proven	RR = 0.47 (0.29–0.78)
31–33 ng/ml	66–77		Adj: age, Wt, Ht, drugs, basal 25D and Ca absorption, comorb, smoking	RR = 0.70 (0.51–0.96)
Bischoff-Ferrari et al. (256).   Positive, women only.   3 yr   27–33 ng/ml	445 M, F >65	D3 700 + Ca 500 vs. Ca alone	Falls (self-report); ↑ proven Adj: age, sex, BMI, Ca intake, CrCl, comorb, basal 25D and PTH, activity, ETOH, smoking	↓ falls, women only OR = 0.54 (0.30–0.97)
Dawson-Hughes et al. (257)   Positive fracture, adverse falls ♀. 3 yr   27–33 ng/ml	389 M, F >65	D3 700 + Ca 500 vs. Ca alone	Fracture, falls (self-report), BMD ↑ Proven Adj: nil	↑ falls in women ↓ fracture (nonvertebral) Falls data not shown
Dukas et al. (374)   Positive, post hoc subgroup. 36 wk   28–30 ng/ml	378 M, F >70	1 μg 1α−OHD3 daily vs. placebo	Falls Not proven Adj: age, BMI, sex falls, activity, CCMI, drugs, heart rate, Ca intake, biochemistry	Ca intake >512 mg/d ↓ fallers OR = 0.46 (0.22–0.99) CrCl < 65, ↓falls OR = 0.29 (0.09–0.88)
Graafmans et al. (263)	354	D3 400 vs. placebo	Falls (self-reported)	No change
Negative. 28 wk	M, F		Not proven	OR = 1
NR. NH	>70		Adj: nil
Prince et al. (260)	302	D2 1000 + Ca 1000 vs. Ca alone	Falls (self-report)	Cal ± D ↓ risk
Positive 1 yr	F 70–90		↑ Proven	OR = 0.61 (0.37–0.99)
<24 ng/ml			Adj: Ht
Pfeifer et al. (258)   Positive. 12 + 8 months   <31 ng/ml	242 M, F 77	D3 800 + Ca 1000 vs. Ca alone	Falls, quad strength, sway, TUAG ↑ Proven Adj: nil	↓ falls RR = 0.73 (0.54–0.96) ↑strength, ↓sway, ↓TUAG
Burleigh et al. (375)	205	D3 800 + Ca 1200 vs. Ca alone	Falls (staff report)	No change
Negative 30 d	M, F		Not proven	RR = 0.82
8.8. ng/ml AGU	84		Adj: nil
Berggren et al. (376)   Trend 1 yr   NR. fracture NOF	199 M, F 82	D3 800 + Ca 1000 + falls prevention vs. normal care	Falls Not proven Adj: dementia and depression	Trend to ↓ falls, P = 0.063 IRR = 0.64 (0.40–1.02)
Harwood et al. (377)   Positive 1 yr   ∼12 ng/ml. fracture hip	150 F 81	D2 300,000 im + Ca 1000 vs. D3 800 + Ca vs. Ca	Falls, 25D, PTH ↑ Proven Adj: age, fracture, BMD, biochemistry, prefracture mobility	↓ falls 0.48 (0.26–0.90)
Pfeifer et al. (262)   Positive 1 yr   <20 ng/ml	148 F 74	D3 800 + Ca 1200 vs. Ca alone	Falls, body sway ↑ Proven Adj: nil	↓ falls in calcium + D group 0.24 vs. 0.45. ↓ sway
Broe et al. (264)	124	D2 200, 400, 600, or 800 or placebo	Falls (staff report)	800 IU ↓ falls vs. all others
Positive, post hoc subgroup. 5 months	M, F 89		↑ Only in the 800 group Adj: age, multivitamin use	IRR = 0.28 (0.11–0.75)
19.5 ng/ml NH
Bischoff et al. (259)   Positive 6w + 12 wk   <31 ng/ml. Inst	122 F 85	D3 800 + Ca 1200 vs. Ca alone	Falls, TUAG, knee + grip strength ↑ Proven Adj: age, falls, basal 1,25D and 25D, observation time	↓ falls, muscle function improved OR = 49% (14–71%)
Sato et al. (85)	96	D2 1000 vs. placebo	Falls, strength, biopsy	↓ falls, increased type II fibers
Positive 8 w + 2 yr	F		↑ Proven	RR = 0.6 (0.4–0.8)
<10 ng/ml	74		Adj: falls, age, Ht, Wt, BMI, strength, basal 25D, 1,25D, PTH, biopsy, walking aid
Sato et al. (378) Positive fracture Negative falls. 18 months 11 ng/ml	96 M, F 71	1 μg 1α−OHD3 vs. placebo	Fracture, falls, BMD, PTH Only 1,25D Adj: nil	↓ nonvertebral fracture, falls no change

Doses for vitamin D and calcium are daily and oral unless stated otherwise. Adj:, Adjusted for; AGU, acute geriatric unit; BI, Barthel index; CCMI, Charlson comorbity index; CrCl, creatinine clearance (ml/min); E/P, estrogen plus progesterone; ETOH, alcohol use; F, female; HR, hazard ratio; Ht, height; Inst, institutionalized; IRR, incidence rate ratio; ITT, intention-to-treat analysis; M, male; NA, not applicable; NH, nursing home; NR, not reported; OR, odds raito; PASE, physical activity scale for the elderly; QOL, quality of life; RR, relative risk; Wt, weight.

Table 5.

Interventional studies assessing the effects of vitamin D supplementation on the incidence of falls (listed in order of number of study participants, highest to lowest)

Study (Ref.), Positive vs. Negative, Duration, Basal 25D, Other	n, Sex, Age	Vitamin D (IU), Ca (mg)	Outcome Proven ↑25D, Adjustments	Main Results, RR/OR/HR/IRR/NNT where given
Larsen et al. (254)	9605	D3 400 + Ca 1000 vs. home visit vs. nil	Severe falls, not proven	12% decrease
Positive 3 yr NR	F >66		Adj: age, marital status, intervention	RR = 0.88; (0.79–0.98) NNT 9
Arden et al. (369)	6641	D2 im, 300,000/yr vs. placebo	Falls, fracture, knee pain	No change
Negative 3 yr	M, F		Not proven
NR	>75		Adj: treatment
Grant et al. (265)	5292	D3 + Ca 1000 vs.	Fracture, falls	No change
Negative 24–62 months	M, F	D3 800 vs.	↑ Proven	HR = 0.97
15 ng/ml (n = 16) Post fracture	>70	placebo	Adj: minimization variables
Law et al. (370)	3717	D2 100,000/3 months vs. placebo	Fracture, falls; ↑ proven	No change
Negative 10 months	M, F		Adj: age, sex, time in the trial, cluster	RR = 1.09
19 ng/ml (47) (n = 16). Inst	85
Porthouse et al. (266)   Negative 25 months   NR. Inst	3314 M, F >70	D3 800 + Ca 1000 + leaflet vs. leaflet	Fracture, falls, QOL Not proven Adj: practice	No change
Chapuy et al. (371)   Positive 18 months   13–16 ng/ml. Inst	3270 M, F 84	D3 800 + Ca 1200 vs. Ca alone	Fracture, 25OHD, PTH Yes Adj:nil	99% fracture from a fall ↓ fracture. Falls risk NR
Sanders et al. (267)	2256	D3 500,000/yr vs. placebo	Fracture, falls; ↑ proven	Higher falls and fracture
Adverse 4–6 yr   20 (49)	F >70		Adj: nil	RR = 1.15 (1.02–1.30) RR fracture = 1.26 (1.0–1.59)
Glendenning et al. (290)	686	D3 150,000 /3m vs. placebo	Falls, TUAG, grip	No changes
Negative 9 months	F		↑ Proven	OR = 1.06
26 ng/ml (n = 40)	77		Adj: age, falls, follow-up
Flicker et al. (255)   Positive, post hoc subgroup. 2 yr   <24 (89%). Inst	625 M, F 83	D2 10,000/wk + Ca 600 then D2 1,000/d + Ca vs. Ca alone	Fracture, falls Not proven Adj: Wt, cognition, drugs, level of care, wandering	Compliant ↓ falls risk IRR = 0.63 (0.48–0.82)
Sambrook et al. (253)   Positive, post hoc subgroup. 12 m   13 ng/ml. NH	602 M, F >70	Extra 30–40 min/d sunlight + Ca 600 vs. nil	Change in 25OHD and falls Not proven Adj: age, sex, falls, balance, comorb, cognition, incontinence, care level	Compliant ↓falls risk IRR = 0.52 (0.31–0.88)
Chapuy et al. (372)	583	D3 800 + Ca 1200 vs.	Fracture, 25OHD, PTH	No change
Negative 2 yr	F	D3 800 vs. placebo vs. Ca alone	↑ Proven
<20 (79%). Inst	85		Adj: nil
Gallagher et al. (373)	489	1,25D 0.5 μg/d vs. placebo ± E/P	Falls	↓ falls. CrCl < or >60
Positive 3 yr	F		Not proven	RR = 0.47 (0.29–0.78)
31–33 ng/ml	66–77		Adj: age, Wt, Ht, drugs, basal 25D and Ca absorption, comorb, smoking	RR = 0.70 (0.51–0.96)
Bischoff-Ferrari et al. (256).   Positive, women only.   3 yr   27–33 ng/ml	445 M, F >65	D3 700 + Ca 500 vs. Ca alone	Falls (self-report); ↑ proven Adj: age, sex, BMI, Ca intake, CrCl, comorb, basal 25D and PTH, activity, ETOH, smoking	↓ falls, women only OR = 0.54 (0.30–0.97)
Dawson-Hughes et al. (257)   Positive fracture, adverse falls ♀. 3 yr   27–33 ng/ml	389 M, F >65	D3 700 + Ca 500 vs. Ca alone	Fracture, falls (self-report), BMD ↑ Proven Adj: nil	↑ falls in women ↓ fracture (nonvertebral) Falls data not shown
Dukas et al. (374)   Positive, post hoc subgroup. 36 wk   28–30 ng/ml	378 M, F >70	1 μg 1α−OHD3 daily vs. placebo	Falls Not proven Adj: age, BMI, sex falls, activity, CCMI, drugs, heart rate, Ca intake, biochemistry	Ca intake >512 mg/d ↓ fallers OR = 0.46 (0.22–0.99) CrCl < 65, ↓falls OR = 0.29 (0.09–0.88)
Graafmans et al. (263)	354	D3 400 vs. placebo	Falls (self-reported)	No change
Negative. 28 wk	M, F		Not proven	OR = 1
NR. NH	>70		Adj: nil
Prince et al. (260)	302	D2 1000 + Ca 1000 vs. Ca alone	Falls (self-report)	Cal ± D ↓ risk
Positive 1 yr	F 70–90		↑ Proven	OR = 0.61 (0.37–0.99)
<24 ng/ml			Adj: Ht
Pfeifer et al. (258)   Positive. 12 + 8 months   <31 ng/ml	242 M, F 77	D3 800 + Ca 1000 vs. Ca alone	Falls, quad strength, sway, TUAG ↑ Proven Adj: nil	↓ falls RR = 0.73 (0.54–0.96) ↑strength, ↓sway, ↓TUAG
Burleigh et al. (375)	205	D3 800 + Ca 1200 vs. Ca alone	Falls (staff report)	No change
Negative 30 d	M, F		Not proven	RR = 0.82
8.8. ng/ml AGU	84		Adj: nil
Berggren et al. (376)   Trend 1 yr   NR. fracture NOF	199 M, F 82	D3 800 + Ca 1000 + falls prevention vs. normal care	Falls Not proven Adj: dementia and depression	Trend to ↓ falls, P = 0.063 IRR = 0.64 (0.40–1.02)
Harwood et al. (377)   Positive 1 yr   ∼12 ng/ml. fracture hip	150 F 81	D2 300,000 im + Ca 1000 vs. D3 800 + Ca vs. Ca	Falls, 25D, PTH ↑ Proven Adj: age, fracture, BMD, biochemistry, prefracture mobility	↓ falls 0.48 (0.26–0.90)
Pfeifer et al. (262)   Positive 1 yr   <20 ng/ml	148 F 74	D3 800 + Ca 1200 vs. Ca alone	Falls, body sway ↑ Proven Adj: nil	↓ falls in calcium + D group 0.24 vs. 0.45. ↓ sway
Broe et al. (264)	124	D2 200, 400, 600, or 800 or placebo	Falls (staff report)	800 IU ↓ falls vs. all others
Positive, post hoc subgroup. 5 months	M, F 89		↑ Only in the 800 group Adj: age, multivitamin use	IRR = 0.28 (0.11–0.75)
19.5 ng/ml NH
Bischoff et al. (259)   Positive 6w + 12 wk   <31 ng/ml. Inst	122 F 85	D3 800 + Ca 1200 vs. Ca alone	Falls, TUAG, knee + grip strength ↑ Proven Adj: age, falls, basal 1,25D and 25D, observation time	↓ falls, muscle function improved OR = 49% (14–71%)
Sato et al. (85)	96	D2 1000 vs. placebo	Falls, strength, biopsy	↓ falls, increased type II fibers
Positive 8 w + 2 yr	F		↑ Proven	RR = 0.6 (0.4–0.8)
<10 ng/ml	74		Adj: falls, age, Ht, Wt, BMI, strength, basal 25D, 1,25D, PTH, biopsy, walking aid
Sato et al. (378) Positive fracture Negative falls. 18 months 11 ng/ml	96 M, F 71	1 μg 1α−OHD3 vs. placebo	Fracture, falls, BMD, PTH Only 1,25D Adj: nil	↓ nonvertebral fracture, falls no change

Study (Ref.), Positive vs. Negative, Duration, Basal 25D, Other	n, Sex, Age	Vitamin D (IU), Ca (mg)	Outcome Proven ↑25D, Adjustments	Main Results, RR/OR/HR/IRR/NNT where given
Larsen et al. (254)	9605	D3 400 + Ca 1000 vs. home visit vs. nil	Severe falls, not proven	12% decrease
Positive 3 yr NR	F >66		Adj: age, marital status, intervention	RR = 0.88; (0.79–0.98) NNT 9
Arden et al. (369)	6641	D2 im, 300,000/yr vs. placebo	Falls, fracture, knee pain	No change
Negative 3 yr	M, F		Not proven
NR	>75		Adj: treatment
Grant et al. (265)	5292	D3 + Ca 1000 vs.	Fracture, falls	No change
Negative 24–62 months	M, F	D3 800 vs.	↑ Proven	HR = 0.97
15 ng/ml (n = 16) Post fracture	>70	placebo	Adj: minimization variables
Law et al. (370)	3717	D2 100,000/3 months vs. placebo	Fracture, falls; ↑ proven	No change
Negative 10 months	M, F		Adj: age, sex, time in the trial, cluster	RR = 1.09
19 ng/ml (47) (n = 16). Inst	85
Porthouse et al. (266)   Negative 25 months   NR. Inst	3314 M, F >70	D3 800 + Ca 1000 + leaflet vs. leaflet	Fracture, falls, QOL Not proven Adj: practice	No change
Chapuy et al. (371)   Positive 18 months   13–16 ng/ml. Inst	3270 M, F 84	D3 800 + Ca 1200 vs. Ca alone	Fracture, 25OHD, PTH Yes Adj:nil	99% fracture from a fall ↓ fracture. Falls risk NR
Sanders et al. (267)	2256	D3 500,000/yr vs. placebo	Fracture, falls; ↑ proven	Higher falls and fracture
Adverse 4–6 yr   20 (49)	F >70		Adj: nil	RR = 1.15 (1.02–1.30) RR fracture = 1.26 (1.0–1.59)
Glendenning et al. (290)	686	D3 150,000 /3m vs. placebo	Falls, TUAG, grip	No changes
Negative 9 months	F		↑ Proven	OR = 1.06
26 ng/ml (n = 40)	77		Adj: age, falls, follow-up
Flicker et al. (255)   Positive, post hoc subgroup. 2 yr   <24 (89%). Inst	625 M, F 83	D2 10,000/wk + Ca 600 then D2 1,000/d + Ca vs. Ca alone	Fracture, falls Not proven Adj: Wt, cognition, drugs, level of care, wandering	Compliant ↓ falls risk IRR = 0.63 (0.48–0.82)
Sambrook et al. (253)   Positive, post hoc subgroup. 12 m   13 ng/ml. NH	602 M, F >70	Extra 30–40 min/d sunlight + Ca 600 vs. nil	Change in 25OHD and falls Not proven Adj: age, sex, falls, balance, comorb, cognition, incontinence, care level	Compliant ↓falls risk IRR = 0.52 (0.31–0.88)
Chapuy et al. (372)	583	D3 800 + Ca 1200 vs.	Fracture, 25OHD, PTH	No change
Negative 2 yr	F	D3 800 vs. placebo vs. Ca alone	↑ Proven
<20 (79%). Inst	85		Adj: nil
Gallagher et al. (373)	489	1,25D 0.5 μg/d vs. placebo ± E/P	Falls	↓ falls. CrCl < or >60
Positive 3 yr	F		Not proven	RR = 0.47 (0.29–0.78)
31–33 ng/ml	66–77		Adj: age, Wt, Ht, drugs, basal 25D and Ca absorption, comorb, smoking	RR = 0.70 (0.51–0.96)
Bischoff-Ferrari et al. (256).   Positive, women only.   3 yr   27–33 ng/ml	445 M, F >65	D3 700 + Ca 500 vs. Ca alone	Falls (self-report); ↑ proven Adj: age, sex, BMI, Ca intake, CrCl, comorb, basal 25D and PTH, activity, ETOH, smoking	↓ falls, women only OR = 0.54 (0.30–0.97)
Dawson-Hughes et al. (257)   Positive fracture, adverse falls ♀. 3 yr   27–33 ng/ml	389 M, F >65	D3 700 + Ca 500 vs. Ca alone	Fracture, falls (self-report), BMD ↑ Proven Adj: nil	↑ falls in women ↓ fracture (nonvertebral) Falls data not shown
Dukas et al. (374)   Positive, post hoc subgroup. 36 wk   28–30 ng/ml	378 M, F >70	1 μg 1α−OHD3 daily vs. placebo	Falls Not proven Adj: age, BMI, sex falls, activity, CCMI, drugs, heart rate, Ca intake, biochemistry	Ca intake >512 mg/d ↓ fallers OR = 0.46 (0.22–0.99) CrCl < 65, ↓falls OR = 0.29 (0.09–0.88)
Graafmans et al. (263)	354	D3 400 vs. placebo	Falls (self-reported)	No change
Negative. 28 wk	M, F		Not proven	OR = 1
NR. NH	>70		Adj: nil
Prince et al. (260)	302	D2 1000 + Ca 1000 vs. Ca alone	Falls (self-report)	Cal ± D ↓ risk
Positive 1 yr	F 70–90		↑ Proven	OR = 0.61 (0.37–0.99)
<24 ng/ml			Adj: Ht
Pfeifer et al. (258)   Positive. 12 + 8 months   <31 ng/ml	242 M, F 77	D3 800 + Ca 1000 vs. Ca alone	Falls, quad strength, sway, TUAG ↑ Proven Adj: nil	↓ falls RR = 0.73 (0.54–0.96) ↑strength, ↓sway, ↓TUAG
Burleigh et al. (375)	205	D3 800 + Ca 1200 vs. Ca alone	Falls (staff report)	No change
Negative 30 d	M, F		Not proven	RR = 0.82
8.8. ng/ml AGU	84		Adj: nil
Berggren et al. (376)   Trend 1 yr   NR. fracture NOF	199 M, F 82	D3 800 + Ca 1000 + falls prevention vs. normal care	Falls Not proven Adj: dementia and depression	Trend to ↓ falls, P = 0.063 IRR = 0.64 (0.40–1.02)
Harwood et al. (377)   Positive 1 yr   ∼12 ng/ml. fracture hip	150 F 81	D2 300,000 im + Ca 1000 vs. D3 800 + Ca vs. Ca	Falls, 25D, PTH ↑ Proven Adj: age, fracture, BMD, biochemistry, prefracture mobility	↓ falls 0.48 (0.26–0.90)
Pfeifer et al. (262)   Positive 1 yr   <20 ng/ml	148 F 74	D3 800 + Ca 1200 vs. Ca alone	Falls, body sway ↑ Proven Adj: nil	↓ falls in calcium + D group 0.24 vs. 0.45. ↓ sway
Broe et al. (264)	124	D2 200, 400, 600, or 800 or placebo	Falls (staff report)	800 IU ↓ falls vs. all others
Positive, post hoc subgroup. 5 months	M, F 89		↑ Only in the 800 group Adj: age, multivitamin use	IRR = 0.28 (0.11–0.75)
19.5 ng/ml NH
Bischoff et al. (259)   Positive 6w + 12 wk   <31 ng/ml. Inst	122 F 85	D3 800 + Ca 1200 vs. Ca alone	Falls, TUAG, knee + grip strength ↑ Proven Adj: age, falls, basal 1,25D and 25D, observation time	↓ falls, muscle function improved OR = 49% (14–71%)
Sato et al. (85)	96	D2 1000 vs. placebo	Falls, strength, biopsy	↓ falls, increased type II fibers
Positive 8 w + 2 yr	F		↑ Proven	RR = 0.6 (0.4–0.8)
<10 ng/ml	74		Adj: falls, age, Ht, Wt, BMI, strength, basal 25D, 1,25D, PTH, biopsy, walking aid
Sato et al. (378) Positive fracture Negative falls. 18 months 11 ng/ml	96 M, F 71	1 μg 1α−OHD3 vs. placebo	Fracture, falls, BMD, PTH Only 1,25D Adj: nil	↓ nonvertebral fracture, falls no change

Doses for vitamin D and calcium are daily and oral unless stated otherwise. Adj:, Adjusted for; AGU, acute geriatric unit; BI, Barthel index; CCMI, Charlson comorbity index; CrCl, creatinine clearance (ml/min); E/P, estrogen plus progesterone; ETOH, alcohol use; F, female; HR, hazard ratio; Ht, height; Inst, institutionalized; IRR, incidence rate ratio; ITT, intention-to-treat analysis; M, male; NA, not applicable; NH, nursing home; NR, not reported; OR, odds raito; PASE, physical activity scale for the elderly; QOL, quality of life; RR, relative risk; Wt, weight.

a. Sunlight therapy.

In a study of 602 residents of aged-care facilities, those who complied with a daily regimen of increased sunlight exposure had fewer falls than those randomized to the control group (253). Compliance was surprisingly poor despite the use of sunlight officers who visited the facilities (median adherence was 26%). Thus, on intention-to-treat analysis, the study was underpowered, and no effects were seen. The authors concluded that vitamin D supplementation was a more practical approach to reduce falls in residential care. It should also be noted that sunlight exposure during the early morning hours rather than at midday when UV levels are highest might not have been sufficiently effective in the synthesis of vitamin D.

b. Intervention studies: non-placebo controlled.

The combination of daily 400 IU vitamin D₃ plus 1000 mg calcium reduced severe falls requiring admission in 5063 community-dwelling city residents above the age of 66 yr in Denmark (254). The number needed to treat was nine.

c. Intervention studies: placebo controlled.

A reduced incidence of falls, regardless of baseline 25D, was seen in a randomized trial of vitamin D supplementation (255). Among 625 older residents of assisted-living facilities, those who received calcium (600 mg daily) and vitamin D₂ (initially 10,000 IU once weekly and then 1,000 IU daily) for 2 yr had a lower rate of falls compared with those receiving calcium alone. However, the rate of ever falling was not different, implying that the benefits were among repeat fallers. On subgroup analysis of compliant participants (defined as taking >50% of the doses, n = 540) the risk of ever falling was also significantly lower. The number needed to treat to prevent one fall per year was eight, similar to the above open-label study.

A 3-yr double-blinded randomized study examined combined supplementation with vitamin D₃ (700 IU) and calcium citrate malate (500 mg) vs. placebo in 445 community-dwelling older individuals (256). By intention-to-treat analysis, combined therapy was not effective. A subgroup analysis of the women found a significant reduction in the incidence of falls that was most pronounced in those who were less active. Inter-gender differences in muscle mass were postulated to lead to greater susceptibility for falls among this particular group. The trial was not originally powered to detect effect modification by sex and activity levels, and falls were also a secondary outcome. The primary outcome examined bone density, which was significantly improved (257). In another study, 242 community-dwelling older individuals were randomized to receive calcium (1000 mg daily) with or without vitamin D₃ (800 IU daily) for 1 yr and then followed 8 months without treatment but continuing blinding to treatment (258). On intention-to-treat analysis, subjects on dual supplementation reported 27% fewer falls at 1 yr and 39% fewer falls at 20 months.

Among 122 older women in long-stay geriatric care who received calcium (1200 mg/d) with or without vitamin D₃ (800 IU/d), those on dual supplementation had significantly fewer falls during the 12-wk treatment period compared with the preceding 6-wk observation period. There was no difference in the proportion who fell at all, but people who fell the most appeared to obtain the greatest benefit (259).

In a particularly vulnerable group, namely older individuals with poststroke hemiplegia, a significant reduction in the number of falls per person and the total number of repeat fallers was seen among 48 women receiving vitamin D₂ (1000 IU daily) vs. controls who received placebo for 2 yr (85). The study included biopsies of the unaffected side and reported that the baseline proportion and diameter of type II muscle fibers were significant independent predictors for falls over the 2 yr. In demonstrating significant improvements in these parameters in a subset of individuals who received vitamin D supplementation for 2 yr, they offered a mechanistic explanation for the reduction in falls.

By contrast, recurrent fallers were the least likely to benefit from supplementation in another study (260). Community-dwelling ambulant older women were randomized to receive calcium citrate (1000 mg daily) and either vitamin D₂ (1000 IU) or placebo for 1 yr. After adjusting for height, which was not equal at baseline, the vitamin D group had a 19% lower risk of a single fall compared with controls. The effect was most pronounced in winter/spring rather than in summer/autumn. It was calculated that 25D levels over 22 ng/ml (54 nmol/liter) were adequate for the benefit. The results were not statistically significant without height correction.

Another study that specifically targeted vitamin D-insufficient older individuals [25D <20 ng/ml (50 nmol/liter)] reported that 800 IU vitamin D₃ and 1200 mg calcium daily decreased falls per subject compared with the 148 controls who received calcium alone (261). One noncompliant individual was excluded from analysis. The authors propose that the mechanism relates to a significant improvement in body sway at 8 wk (261, 262). Sagittal body sway improved with treatment, but frontal sway improved in both groups (261).

d. Negative randomized studies and falls.

A number of randomized studies have also failed to demonstrate an effect of vitamin D supplementation upon falls.

Among 354 older persons in The Netherlands who were randomized to receive vitamin D₃ (400 IU) or placebo for 28 wk, impaired mobility was the major predictor of falls, and vitamin D treatment had no significant effect (263). This study had marked patient heterogeneity with inclusion of both institutionalized and community-dwelling persons.

A positive effect of vitamin D supplementation on falls risk was reported by Broe et al. (264) among the subgroup of 124 nursing home residents receiving high-dose vitamin D (800 IU/d) but not in the 600-, 400-, or 200-IU groups. The risk of falling was lower if those receiving 800 IU vitamin D₂ were compared with the combined group of smaller doses (200, 400, or 600 IU) and placebo. There was no suggestion of a normal dose-response curve with the lower doses actually having nonsignificantly higher fall rates compared with placebo (0 IU, 44%; 200 IU, 58%; 400 IU, 60%; 600 IU, 60%; 800 IU, 20%).

A large study of 5292 subjects over 70 yr of age with a recent minimal-trauma fracture did not find a beneficial effect of 800 IU of vitamin D₃ on falls over 26–62 months (265). Falls were a secondary endpoint with information collected only for the week before each 4-monthly questionnaire. Compliance (patients taking 80% or more of tablets) was poor (<45% at 2 yr); however, there was also no benefit if only compliant patients were examined. Baseline levels were measured in approximately 1% of patients (n = 60) and were 15.2 ng/ml (38 nmol/liter).

Another study in 3314 older women living in nursing homes did not find fewer falls among those randomized to receive a combination of vitamin D₃ (800 IU), calcium (1000 mg), and a falls prevention leaflet over 25 months compared with those receiving the leaflet alone (266). Falls were also a secondary outcome in this study.

In reaction to generally poor adherence to daily regimens of vitamin D supplementation as described by a number of these reports, other studies have examined the efficacy of infrequent high-dose vitamin D supplementation. In one widely reported study of 2256 community-dwelling women over 70 yr of age, an annual oral dose of 500,000 IU of vitamin D₃ for 3–5 yr appeared to increase the risk of falls, particularly in the first 3 months after the vitamin D dose (267). The median baseline 25D concentration was 21.2 ng/ml (53 nmol/liter), and 1 month after treatment, the median was 48 ng/ml (120 nmol/liter).

Another study using 300,000 IU, given annually by im injection, reported no effect on falls among 9440 older individuals (268). No benefit was observed in any subgroup.

3. Meta-analyses and falls

Substantial heterogeneity among these randomized trials with regard to differences in study populations, variable treatment durations, and regimens of supplemental vitamin D and whether or not calcium was coadministered together with inconsistencies in the identification and analysis of falls among studies (e.g. falls per subject, number of falls, and number of fallers) makes collective assessment of these data difficult. Nevertheless, several meta-analyses have been published and are the subject of debate (23, 29, 30, 269–272).

Most recently, a meta-analysis reported on 26 randomized trials that enrolled 45,782 participants, mainly elderly females (23). Studies were not excluded for lack of double randomization or strict definition of falls; hence, there were a substantially larger number of included individuals than in earlier meta-analyses. Vitamin D use was associated with statistically significant reduction in the risk of falls. However, there was no difference among those receiving higher doses (>800 IU) vs. lower doses. Vitamin D appeared to be effective in both community-dwelling and institutionalized people and in those receiving vitamin D₂ or D₃. Perhaps reassuringly, the reduction in falls was most prominent in patients who were vitamin D deficient at baseline. Studies in which calcium was coadministered with vitamin D showed a greater effect than those where vitamin D alone was given. Falls reduction in studies without calcium coadministration did not reach statistical significance. Calcium alone was the placebo in most of the combination studies.

Therefore, despite substantial heterogeneity among studies, vitamin D supplementation is probably effective in conjunction with calcium in the prevention of falls among older individuals. The positive impact of vitamin D and calcium supplementation on fall prevention appears to be best among those who are vitamin D deficient at baseline. We recommend consideration of vitamin D plus calcium therapy in people over 65 yr of age with baseline deficiency. However, appropriate supplemental dose of vitamin D and target serum levels required to prevent falls remain hotly debated issues.

F. Muscle strength and physical performance

Many studies have examined the specific effects of vitamin D on measures of muscle function and physical performance. Comparing these studies is made very difficult by the variety of outcome measures used to assess muscle function.

1. Observational studies

A number of cross-sectional studies have reported associations between 25D levels and various parameters related to muscle function including handgrip, lower limb strength, balance, 6-min walk distance, and gait speed (273–275), although not all such studies have supported the association after multivariate adjustment (276, 277). These are summarized in Table 6.

Table 6.

Cross-sectional studies assessing the correlation between vitamin D levels and muscle function (listed in order of number of study participants, highest to lowest)

Study (Ref.)	n	Sex	Age (yr)	Positive or negative	Other	Muscle function tests	Findings	Adjustments
Bischoff-Ferrari et al. (278)	4100	M, F	60–90	Positive	Ambulatory	8-ft. walk, repeated STST	25D 40–94 nmol/liter, better function vs. <40 nmol/liter	Sex, age, BMI, ethnicity, SES, Ca intake, comorb, walking device, month, activity
Wicherts et al. (279)	1234	M, F	>65	Positive	Ambulatory	Physical performance score	Poorer with 25D <25 and 25–50 vs. >75 nmol/liter	Age, sex, chronic diseases, urbanization, BMI, ETOH
Gerdhem et al. (379)	986	F	78	Positive	Ambulatory	Gait speed, Romberg test, thigh strength, activity	25D correlated with all outcomes (activity threshold 87 nmol/liter)	BMI, weight, height, BMD, hours spent outdoors, activity
Houston et al. (275)	976	F	>65	Positive	Ambulatory	SPPB (walk speed, STST, balance), grip	25D <10 ng/ml, ↓ SPPB; 25D <20 ng/ml, ↓ grip	SES, smoking, BMI, activity, cognition, season
Marantes et al. (306)	667	M, F	21–97	Positive post hoc, subgroup		Lean mass, muscle mass, grip strength, knee extension	25D, no associations; ↓ 1,25D correlated with ↓ muscle mass and knee strength in <65-yr-old F	Age, height, activity, season of the baseline visit, fat mass
Annweiler et al. (380)	440	F	>70	Negative	CommD	Handgrip and quadriceps strength	No significant associations	Age, chronic diseases, BMI, Ca use, activity, serum Ca, CrCl
Beauchet et al. (381)	411	M, F	70	Positive, one measure	Ambulatory	STV, sway, grip strength, other	25D <25 nmol/liter, worse STV only	Age, sex, drugs, cognition, falls last year
Mowé et al. (382)	349	M, F	70–91	Positive, some measures	Hosp (70%), CommD	Falls, grip and proximal strength, walking	25D correlated with strength, activity, and absence of falls	BMI, age, serum albumin, heart disease
Bischoff et al. (277)	319	M, F	74–77	Positive	Ambulatory	Leg extension power	1,25D correlated with leg extension power	Age, sex, BMI, 1,25D, PTH, 25D
Stein et al. (252)	83	M, F	84	Negative	NH, hostel	Falls before 25D measurement	25D not significant; higher PTH, ↑ falls	Multivariate analysis
Boxer et al. (273)	60	M, F	77	Positive	CF	6-min walk, frailty markers	25D levels correlated with both measures	Age, sex, free T, DHEAS, 25D, PTH, hsCRP, IL-6, cortisol/DHEAS ratio, and NTpro-BNP
Mastaglia et al. (274)	54	F	71	Positive, some measures	Ambulatory	Walk speed, STST, balance, leg strength	25D ≥20 ng/ml, greater knee and hip strength.	Nil
Ducher et al. (308)	16	M	10–19	Negative	Ballet dancers	Injury, DEXA	No correlations	Nil

Study (Ref.)	n	Sex	Age (yr)	Positive or negative	Other	Muscle function tests	Findings	Adjustments
Bischoff-Ferrari et al. (278)	4100	M, F	60–90	Positive	Ambulatory	8-ft. walk, repeated STST	25D 40–94 nmol/liter, better function vs. <40 nmol/liter	Sex, age, BMI, ethnicity, SES, Ca intake, comorb, walking device, month, activity
Wicherts et al. (279)	1234	M, F	>65	Positive	Ambulatory	Physical performance score	Poorer with 25D <25 and 25–50 vs. >75 nmol/liter	Age, sex, chronic diseases, urbanization, BMI, ETOH
Gerdhem et al. (379)	986	F	78	Positive	Ambulatory	Gait speed, Romberg test, thigh strength, activity	25D correlated with all outcomes (activity threshold 87 nmol/liter)	BMI, weight, height, BMD, hours spent outdoors, activity
Houston et al. (275)	976	F	>65	Positive	Ambulatory	SPPB (walk speed, STST, balance), grip	25D <10 ng/ml, ↓ SPPB; 25D <20 ng/ml, ↓ grip	SES, smoking, BMI, activity, cognition, season
Marantes et al. (306)	667	M, F	21–97	Positive post hoc, subgroup		Lean mass, muscle mass, grip strength, knee extension	25D, no associations; ↓ 1,25D correlated with ↓ muscle mass and knee strength in <65-yr-old F	Age, height, activity, season of the baseline visit, fat mass
Annweiler et al. (380)	440	F	>70	Negative	CommD	Handgrip and quadriceps strength	No significant associations	Age, chronic diseases, BMI, Ca use, activity, serum Ca, CrCl
Beauchet et al. (381)	411	M, F	70	Positive, one measure	Ambulatory	STV, sway, grip strength, other	25D <25 nmol/liter, worse STV only	Age, sex, drugs, cognition, falls last year
Mowé et al. (382)	349	M, F	70–91	Positive, some measures	Hosp (70%), CommD	Falls, grip and proximal strength, walking	25D correlated with strength, activity, and absence of falls	BMI, age, serum albumin, heart disease
Bischoff et al. (277)	319	M, F	74–77	Positive	Ambulatory	Leg extension power	1,25D correlated with leg extension power	Age, sex, BMI, 1,25D, PTH, 25D
Stein et al. (252)	83	M, F	84	Negative	NH, hostel	Falls before 25D measurement	25D not significant; higher PTH, ↑ falls	Multivariate analysis
Boxer et al. (273)	60	M, F	77	Positive	CF	6-min walk, frailty markers	25D levels correlated with both measures	Age, sex, free T, DHEAS, 25D, PTH, hsCRP, IL-6, cortisol/DHEAS ratio, and NTpro-BNP
Mastaglia et al. (274)	54	F	71	Positive, some measures	Ambulatory	Walk speed, STST, balance, leg strength	25D ≥20 ng/ml, greater knee and hip strength.	Nil
Ducher et al. (308)	16	M	10–19	Negative	Ballet dancers	Injury, DEXA	No correlations	Nil

CF, Cardiac failure (ejection fraction <40%); CommD, community dwelling; comorb, comorbid conditions; CrCl, creatinine clearance; DHEAS, dehydroepiandrosterone sulfate; ETOH, alcohol use; free T, percent free testosterone; Hosp, recently hospitalized; hsCRP, high-sensitivity C-reactive protein; NH, nursing home; NT-proBNP, N-terminal pro-brain natritretic peptide; SES, socioeconomic status; SPPB, short physical performance battery; STV, stride time variability.

Table 6.

Cross-sectional studies assessing the correlation between vitamin D levels and muscle function (listed in order of number of study participants, highest to lowest)

Study (Ref.)	n	Sex	Age (yr)	Positive or negative	Other	Muscle function tests	Findings	Adjustments
Bischoff-Ferrari et al. (278)	4100	M, F	60–90	Positive	Ambulatory	8-ft. walk, repeated STST	25D 40–94 nmol/liter, better function vs. <40 nmol/liter	Sex, age, BMI, ethnicity, SES, Ca intake, comorb, walking device, month, activity
Wicherts et al. (279)	1234	M, F	>65	Positive	Ambulatory	Physical performance score	Poorer with 25D <25 and 25–50 vs. >75 nmol/liter	Age, sex, chronic diseases, urbanization, BMI, ETOH
Gerdhem et al. (379)	986	F	78	Positive	Ambulatory	Gait speed, Romberg test, thigh strength, activity	25D correlated with all outcomes (activity threshold 87 nmol/liter)	BMI, weight, height, BMD, hours spent outdoors, activity
Houston et al. (275)	976	F	>65	Positive	Ambulatory	SPPB (walk speed, STST, balance), grip	25D <10 ng/ml, ↓ SPPB; 25D <20 ng/ml, ↓ grip	SES, smoking, BMI, activity, cognition, season
Marantes et al. (306)	667	M, F	21–97	Positive post hoc, subgroup		Lean mass, muscle mass, grip strength, knee extension	25D, no associations; ↓ 1,25D correlated with ↓ muscle mass and knee strength in <65-yr-old F	Age, height, activity, season of the baseline visit, fat mass
Annweiler et al. (380)	440	F	>70	Negative	CommD	Handgrip and quadriceps strength	No significant associations	Age, chronic diseases, BMI, Ca use, activity, serum Ca, CrCl
Beauchet et al. (381)	411	M, F	70	Positive, one measure	Ambulatory	STV, sway, grip strength, other	25D <25 nmol/liter, worse STV only	Age, sex, drugs, cognition, falls last year
Mowé et al. (382)	349	M, F	70–91	Positive, some measures	Hosp (70%), CommD	Falls, grip and proximal strength, walking	25D correlated with strength, activity, and absence of falls	BMI, age, serum albumin, heart disease
Bischoff et al. (277)	319	M, F	74–77	Positive	Ambulatory	Leg extension power	1,25D correlated with leg extension power	Age, sex, BMI, 1,25D, PTH, 25D
Stein et al. (252)	83	M, F	84	Negative	NH, hostel	Falls before 25D measurement	25D not significant; higher PTH, ↑ falls	Multivariate analysis
Boxer et al. (273)	60	M, F	77	Positive	CF	6-min walk, frailty markers	25D levels correlated with both measures	Age, sex, free T, DHEAS, 25D, PTH, hsCRP, IL-6, cortisol/DHEAS ratio, and NTpro-BNP
Mastaglia et al. (274)	54	F	71	Positive, some measures	Ambulatory	Walk speed, STST, balance, leg strength	25D ≥20 ng/ml, greater knee and hip strength.	Nil
Ducher et al. (308)	16	M	10–19	Negative	Ballet dancers	Injury, DEXA	No correlations	Nil

Study (Ref.)	n	Sex	Age (yr)	Positive or negative	Other	Muscle function tests	Findings	Adjustments
Bischoff-Ferrari et al. (278)	4100	M, F	60–90	Positive	Ambulatory	8-ft. walk, repeated STST	25D 40–94 nmol/liter, better function vs. <40 nmol/liter	Sex, age, BMI, ethnicity, SES, Ca intake, comorb, walking device, month, activity
Wicherts et al. (279)	1234	M, F	>65	Positive	Ambulatory	Physical performance score	Poorer with 25D <25 and 25–50 vs. >75 nmol/liter	Age, sex, chronic diseases, urbanization, BMI, ETOH
Gerdhem et al. (379)	986	F	78	Positive	Ambulatory	Gait speed, Romberg test, thigh strength, activity	25D correlated with all outcomes (activity threshold 87 nmol/liter)	BMI, weight, height, BMD, hours spent outdoors, activity
Houston et al. (275)	976	F	>65	Positive	Ambulatory	SPPB (walk speed, STST, balance), grip	25D <10 ng/ml, ↓ SPPB; 25D <20 ng/ml, ↓ grip	SES, smoking, BMI, activity, cognition, season
Marantes et al. (306)	667	M, F	21–97	Positive post hoc, subgroup		Lean mass, muscle mass, grip strength, knee extension	25D, no associations; ↓ 1,25D correlated with ↓ muscle mass and knee strength in <65-yr-old F	Age, height, activity, season of the baseline visit, fat mass
Annweiler et al. (380)	440	F	>70	Negative	CommD	Handgrip and quadriceps strength	No significant associations	Age, chronic diseases, BMI, Ca use, activity, serum Ca, CrCl
Beauchet et al. (381)	411	M, F	70	Positive, one measure	Ambulatory	STV, sway, grip strength, other	25D <25 nmol/liter, worse STV only	Age, sex, drugs, cognition, falls last year
Mowé et al. (382)	349	M, F	70–91	Positive, some measures	Hosp (70%), CommD	Falls, grip and proximal strength, walking	25D correlated with strength, activity, and absence of falls	BMI, age, serum albumin, heart disease
Bischoff et al. (277)	319	M, F	74–77	Positive	Ambulatory	Leg extension power	1,25D correlated with leg extension power	Age, sex, BMI, 1,25D, PTH, 25D
Stein et al. (252)	83	M, F	84	Negative	NH, hostel	Falls before 25D measurement	25D not significant; higher PTH, ↑ falls	Multivariate analysis
Boxer et al. (273)	60	M, F	77	Positive	CF	6-min walk, frailty markers	25D levels correlated with both measures	Age, sex, free T, DHEAS, 25D, PTH, hsCRP, IL-6, cortisol/DHEAS ratio, and NTpro-BNP
Mastaglia et al. (274)	54	F	71	Positive, some measures	Ambulatory	Walk speed, STST, balance, leg strength	25D ≥20 ng/ml, greater knee and hip strength.	Nil
Ducher et al. (308)	16	M	10–19	Negative	Ballet dancers	Injury, DEXA	No correlations	Nil

CF, Cardiac failure (ejection fraction <40%); CommD, community dwelling; comorb, comorbid conditions; CrCl, creatinine clearance; DHEAS, dehydroepiandrosterone sulfate; ETOH, alcohol use; free T, percent free testosterone; Hosp, recently hospitalized; hsCRP, high-sensitivity C-reactive protein; NH, nursing home; NT-proBNP, N-terminal pro-brain natritretic peptide; SES, socioeconomic status; SPPB, short physical performance battery; STV, stride time variability.

In a population-based study of 4100 ambulatory adults aged over 60 yr, an association between serum 25D and lower-extremity function assessed by 8-ft. walk and the repeated sit-to-stand test (STST) was reported (278). The improvements were modest: 3.9% worsening in STST and 5.6% in 8-ft. walk comparing the lowest vs. the highest quintiles of 25D. Interestingly, a trend toward impaired function with longer STST was seen in patients with high normal 25D [>48 ng/ml (120 nmol/liter)] vs. lower levels [16–38 ng/ml (40–94 nmol/liter)].

Significantly poorer physical performance was seen in 1234 older individuals among those with 25D below 10 ng/ml (25 nmol/liter) and 10–20 ng/ml (25–50 nmol/liter) vs. those higher than 30 ng/ml (75 nmol/liter) (279). In a subgroup of 979 participants followed over 3 yr, those with lower 25D levels had significantly higher risk of decline in physical performance compared with those with levels above 30 ng/ml (75 nmol/liter). Those in the intermediate 25D group of 20–30 ng/ml (50–75 nmol/liter) did not display significantly greater rates of decline.

In a prospective study of 1008 older individuals in the Netherlands, baseline 25D below 10 ng/ml (25 nmol/liter) was associated with poorer grip strength and reduced muscle mass on DEXA after 3 yr compared with people with normal levels [>20 ng/ml (50 nmol/liter)] (280). Those in the intermediate 25D group of 10–20 ng/ml (25–50 nmol/liter) demonstrated significantly greater losses of muscle mass without difference in grip strength vs. those with 25D over 20 ng/ml (50 nmol/liter).

An accelerated rate of decline in physical performance over 2.5 yr on timed up and go tests (TUAG) and timed STST were seen among 769 older women with lower baseline 25D (281). However, low 25D levels are associated with frailty (273), so a range of factors not included in adjustment models may confound data interpretation.

A recent study of 714 Chinese men (>65 yr) found no association between baseline 25D levels and changes in performance measures or appendicular skeletal muscle mass over 4 yr (282). These men were not vitamin D deficient [mean baseline 25D = 31 ng/ml (78 nmol/liter)].

2. Nonrandomized studies

Few studies have examined the effect of vitamin D supplementation on muscle function in younger people. Glerup et al. (208) reported a case-control study in which 55 veiled Arabic women with a mean age of 32 and severe vitamin D deficiency [mean 25D = 3 ng/ml (7 nmol/liter)] were compared with 22 Danish women of similar age but higher 25D levels [19 ng/ml (47 nmol/liter)]. At baseline, all parameters of muscle function were significantly lower in the Arabic women. Baseline 25D levels were independently associated with maximal voluntary knee extension. After vitamin D repletion, the Arabic women displayed significant improvements in parameters of muscle function at 3 and 6 months. At 6 months, a subgroup that was retested showed no difference in electrically stimulated muscle function vs. Danish controls. Subjective improvements in muscle and deep bone pain were reported by the treated Arabic women.

3. Randomized controlled studies

The randomized controlled studies are summarized in Table 7. Two studies discussed in Section VI.E and Table 6 [Bischoff et al. (259) and Pfeifer et al. (258)] reported improvements in muscle function as well as decreased falls in those randomized to receive supplemental vitamin D. Over a 12-wk treatment period, those on calcium and vitamin D demonstrated significant improvements in the summed score of knee flexor and extensor strength, grip strength, and TUAG compared with those receiving calcium alone (259). Significant improvements were reported in quadriceps strength and TUAG in another study with reduced falls after 12 months of dual supplements compared with calcium alone (258).

Table 7.

Interventional studies assessing the effects of vitamin D supplementation on muscle function (listed in order of number of study participants, highest to lowest)

Study (Ref.)	n	Sex	Age (yr)	Positive or negative	Duration	Basal 25D [ng/ml (nmol/liter)]	Other	Vitamin D and Ca/other	Outcomes	Adjustments	Main results
Brunner et al. (383)	33,067	F	50–79	Negative	7 yr	NR	WHI study	D3 400 + Ca 1000 mg vs. placebo	Grip, 6-m walk, chair-STS, exercise	Age, WHI group	No improvement
Zhu et al. (286)	302	F	70–90	Positive, post hoc subgroup	1 yr	18 (44)	CommD	D2 1000 + Ca 1000 or Ca alone	Ankle, knee, hip strength, TUAG	NR	Lowest basal tertile ↑ hip and TUAG
Latham et al. (291)	243	M, F	80	Negative	6 months	17 (42)	Adverse outcomes, frail	D3 300,000 by 1 + exercise vs. placebo	Knee strength, balance, TUAG, 4-m walk, falls	NR	Higher rates of injury with intervention
Lips et al. (384)	226	M, F	>70	Positive, one measure	16 wk	6–20 (15–50)	Ambulatory	D3 8400/wk vs. placebo	Body sway, PAS	Basal sway and 25D	Subgroup ↑ basal sway improved
Kukuljan et al. (293)	180	M	50–79	Negative	18 months	34 (86)	CommD	Milk + D3 800 + Ca 1000 mg vs. placebo ± exercise	Sway, step test, lateral pulldown, leg and bench press	NR	No effect
El-Hajj et al. (295)	179	F	10–17	Positive, one measure	1 yr	14 (35)	School	D3 1400 vs. D3 14,000/wk vs. placebo	Grip, lean mass	NR	No effect
Dhesi et al. (284)	139	M, F	≥65	Positive, three measures	6 months	≥12 (30)	Falls	D2 600,000 im once vs. placebo	CRT, AFPT, quadriceps strength, falls	NR	AFPT, CRT, and sway improved
Johnson et al. (385)	109	M, F	>60	Negative	6 months	NR	CommD	D 2000 vs. placebo	Muscle function in arm and leg	NR	No effect
Witham et al. (386)	105	M, F	>70	Negative	20 wk	<20 (50)	CF	D3 100,000, by 2 or placebo	6-min walk, QOL, activity, function	NR	No effect
Grady et al. (294)	98	M, F	>69	Negative	6 months	24 (60)	Ambulatory	1,25D 0.5 μg or placebo	Quads, grip strength	Age, sex, CrCl, strength	No effect
Bunout et al. (283)	96	M, F	>70	Positive, one measure	9 months	12 (30)	Ambulatory	D3 400 + Ca 800 mg vs. Ca alone	Quads, TUAG, walk speed, other	Compliance	Walk speed increased
Glerup et al. (208)	77	F	32–36	Positive	3–6 months	A (n = 55), 7 (17); D, 42 (104)		D2 100,000 im by 6 + 4–600/d + Ca 8–1200 vs. nil in Danes	Knee extensors	NR	Arabic women improved
Ward et al. (287)	73	F	41–74	Positive, one measure	1 yr	<15 (37.5)	School	Four doses of D2 150,000	Jumping, grip, weight, muscle strength	NR	Jump efficiency improved
Janssen et al. (289)	70	F	>65	Negative, baseline correlated	6 months	8–20 (20–50)	CommD	D3 400 + Ca 500 mg vs. nil	Grip and lower limb strength, TUAG, MCT	NR	No effect
Kenny et al. (387)	65	M	76	Negative	6 months	26 (65)	CommD	D3 1000 + Ca 500 mg vs. nil	Grip and leg strength, PAS, supine TST, TUAG, 6-ft. walk, balance	NR	No effect
Corless et al. (292)	63	M, F	82	Negative	40 wk	17.2 (43)	Hosp	D2 9000 vs. nil	ADL score with walking up stairs and on flat	NR	No effect
Moreira-Pfrimer et al. (285)	56	M, F	>60	Positive	6 months	40–46 (100–115)	Frail, LSGC	Ca 1000 + D3 150,000 by 2 + 90,000/month by 4 vs. Ca + placebo	Hip flexor and knee extensor strength	NR	Both improved
Songpatanasilp et al. (288)	42	F	>65	Positive	12 wk	<30 (75)		1α−OHD3 (0.5 μg) + Ca 1500 mg vs. Ca/Placebo	Quadriceps strength	Baseline strength	Improved quadriceps strength
Gupta et al. (388)	40	M, F	32	Positive	6 months	8–10 (21–25)	Asian	Ca 1000 mg + D3 60,000/wk, 12 doses	Grip and calf strength, respiratory pressures, 6-min walk, MRS	Age, sex, basal measures	Improved grip and calf strength and 6-min walk
Gloth et al. (389)	32	M, F	>65	Positive, post hoc subgroup	6 months	<15 (37.5)	Frail, CommD, NH	Ca (no dose) + D2 400 or Ca + D2 100,000/3 months or Ca alone	FEFA score	NR	Subgroup increase 25D >3 ng/ml D improved

Study (Ref.)	n	Sex	Age (yr)	Positive or negative	Duration	Basal 25D [ng/ml (nmol/liter)]	Other	Vitamin D and Ca/other	Outcomes	Adjustments	Main results
Brunner et al. (383)	33,067	F	50–79	Negative	7 yr	NR	WHI study	D3 400 + Ca 1000 mg vs. placebo	Grip, 6-m walk, chair-STS, exercise	Age, WHI group	No improvement
Zhu et al. (286)	302	F	70–90	Positive, post hoc subgroup	1 yr	18 (44)	CommD	D2 1000 + Ca 1000 or Ca alone	Ankle, knee, hip strength, TUAG	NR	Lowest basal tertile ↑ hip and TUAG
Latham et al. (291)	243	M, F	80	Negative	6 months	17 (42)	Adverse outcomes, frail	D3 300,000 by 1 + exercise vs. placebo	Knee strength, balance, TUAG, 4-m walk, falls	NR	Higher rates of injury with intervention
Lips et al. (384)	226	M, F	>70	Positive, one measure	16 wk	6–20 (15–50)	Ambulatory	D3 8400/wk vs. placebo	Body sway, PAS	Basal sway and 25D	Subgroup ↑ basal sway improved
Kukuljan et al. (293)	180	M	50–79	Negative	18 months	34 (86)	CommD	Milk + D3 800 + Ca 1000 mg vs. placebo ± exercise	Sway, step test, lateral pulldown, leg and bench press	NR	No effect
El-Hajj et al. (295)	179	F	10–17	Positive, one measure	1 yr	14 (35)	School	D3 1400 vs. D3 14,000/wk vs. placebo	Grip, lean mass	NR	No effect
Dhesi et al. (284)	139	M, F	≥65	Positive, three measures	6 months	≥12 (30)	Falls	D2 600,000 im once vs. placebo	CRT, AFPT, quadriceps strength, falls	NR	AFPT, CRT, and sway improved
Johnson et al. (385)	109	M, F	>60	Negative	6 months	NR	CommD	D 2000 vs. placebo	Muscle function in arm and leg	NR	No effect
Witham et al. (386)	105	M, F	>70	Negative	20 wk	<20 (50)	CF	D3 100,000, by 2 or placebo	6-min walk, QOL, activity, function	NR	No effect
Grady et al. (294)	98	M, F	>69	Negative	6 months	24 (60)	Ambulatory	1,25D 0.5 μg or placebo	Quads, grip strength	Age, sex, CrCl, strength	No effect
Bunout et al. (283)	96	M, F	>70	Positive, one measure	9 months	12 (30)	Ambulatory	D3 400 + Ca 800 mg vs. Ca alone	Quads, TUAG, walk speed, other	Compliance	Walk speed increased
Glerup et al. (208)	77	F	32–36	Positive	3–6 months	A (n = 55), 7 (17); D, 42 (104)		D2 100,000 im by 6 + 4–600/d + Ca 8–1200 vs. nil in Danes	Knee extensors	NR	Arabic women improved
Ward et al. (287)	73	F	41–74	Positive, one measure	1 yr	<15 (37.5)	School	Four doses of D2 150,000	Jumping, grip, weight, muscle strength	NR	Jump efficiency improved
Janssen et al. (289)	70	F	>65	Negative, baseline correlated	6 months	8–20 (20–50)	CommD	D3 400 + Ca 500 mg vs. nil	Grip and lower limb strength, TUAG, MCT	NR	No effect
Kenny et al. (387)	65	M	76	Negative	6 months	26 (65)	CommD	D3 1000 + Ca 500 mg vs. nil	Grip and leg strength, PAS, supine TST, TUAG, 6-ft. walk, balance	NR	No effect
Corless et al. (292)	63	M, F	82	Negative	40 wk	17.2 (43)	Hosp	D2 9000 vs. nil	ADL score with walking up stairs and on flat	NR	No effect
Moreira-Pfrimer et al. (285)	56	M, F	>60	Positive	6 months	40–46 (100–115)	Frail, LSGC	Ca 1000 + D3 150,000 by 2 + 90,000/month by 4 vs. Ca + placebo	Hip flexor and knee extensor strength	NR	Both improved
Songpatanasilp et al. (288)	42	F	>65	Positive	12 wk	<30 (75)		1α−OHD3 (0.5 μg) + Ca 1500 mg vs. Ca/Placebo	Quadriceps strength	Baseline strength	Improved quadriceps strength
Gupta et al. (388)	40	M, F	32	Positive	6 months	8–10 (21–25)	Asian	Ca 1000 mg + D3 60,000/wk, 12 doses	Grip and calf strength, respiratory pressures, 6-min walk, MRS	Age, sex, basal measures	Improved grip and calf strength and 6-min walk
Gloth et al. (389)	32	M, F	>65	Positive, post hoc subgroup	6 months	<15 (37.5)	Frail, CommD, NH	Ca (no dose) + D2 400 or Ca + D2 100,000/3 months or Ca alone	FEFA score	NR	Subgroup increase 25D >3 ng/ml D improved

Doses for vitamin D and calcium are daily and administered orally (unless stated otherwise). A, Arab women; AFPT, aggregate functional performance time; CF, cardiac failure; CrCl, creatinine clearance; CRT, choice reaction time; CommD, community dwelling; D, Danish women; FEFA, frail elderly functional assessment score; Hosp, in hospital; ITT, intention-to-treat analysis; LSGC, long-stay geriatric care units; MCT, modified Cooper test; MRS, magnetic resonance spectroscopy; Quads, quadriceps strength; PAS, physical activity/performance score; TST, to stand test; WHI, Women's Health Initiative.

Table 7.

Interventional studies assessing the effects of vitamin D supplementation on muscle function (listed in order of number of study participants, highest to lowest)

Study (Ref.)	n	Sex	Age (yr)	Positive or negative	Duration	Basal 25D [ng/ml (nmol/liter)]	Other	Vitamin D and Ca/other	Outcomes	Adjustments	Main results
Brunner et al. (383)	33,067	F	50–79	Negative	7 yr	NR	WHI study	D3 400 + Ca 1000 mg vs. placebo	Grip, 6-m walk, chair-STS, exercise	Age, WHI group	No improvement
Zhu et al. (286)	302	F	70–90	Positive, post hoc subgroup	1 yr	18 (44)	CommD	D2 1000 + Ca 1000 or Ca alone	Ankle, knee, hip strength, TUAG	NR	Lowest basal tertile ↑ hip and TUAG
Latham et al. (291)	243	M, F	80	Negative	6 months	17 (42)	Adverse outcomes, frail	D3 300,000 by 1 + exercise vs. placebo	Knee strength, balance, TUAG, 4-m walk, falls	NR	Higher rates of injury with intervention
Lips et al. (384)	226	M, F	>70	Positive, one measure	16 wk	6–20 (15–50)	Ambulatory	D3 8400/wk vs. placebo	Body sway, PAS	Basal sway and 25D	Subgroup ↑ basal sway improved
Kukuljan et al. (293)	180	M	50–79	Negative	18 months	34 (86)	CommD	Milk + D3 800 + Ca 1000 mg vs. placebo ± exercise	Sway, step test, lateral pulldown, leg and bench press	NR	No effect
El-Hajj et al. (295)	179	F	10–17	Positive, one measure	1 yr	14 (35)	School	D3 1400 vs. D3 14,000/wk vs. placebo	Grip, lean mass	NR	No effect
Dhesi et al. (284)	139	M, F	≥65	Positive, three measures	6 months	≥12 (30)	Falls	D2 600,000 im once vs. placebo	CRT, AFPT, quadriceps strength, falls	NR	AFPT, CRT, and sway improved
Johnson et al. (385)	109	M, F	>60	Negative	6 months	NR	CommD	D 2000 vs. placebo	Muscle function in arm and leg	NR	No effect
Witham et al. (386)	105	M, F	>70	Negative	20 wk	<20 (50)	CF	D3 100,000, by 2 or placebo	6-min walk, QOL, activity, function	NR	No effect
Grady et al. (294)	98	M, F	>69	Negative	6 months	24 (60)	Ambulatory	1,25D 0.5 μg or placebo	Quads, grip strength	Age, sex, CrCl, strength	No effect
Bunout et al. (283)	96	M, F	>70	Positive, one measure	9 months	12 (30)	Ambulatory	D3 400 + Ca 800 mg vs. Ca alone	Quads, TUAG, walk speed, other	Compliance	Walk speed increased
Glerup et al. (208)	77	F	32–36	Positive	3–6 months	A (n = 55), 7 (17); D, 42 (104)		D2 100,000 im by 6 + 4–600/d + Ca 8–1200 vs. nil in Danes	Knee extensors	NR	Arabic women improved
Ward et al. (287)	73	F	41–74	Positive, one measure	1 yr	<15 (37.5)	School	Four doses of D2 150,000	Jumping, grip, weight, muscle strength	NR	Jump efficiency improved
Janssen et al. (289)	70	F	>65	Negative, baseline correlated	6 months	8–20 (20–50)	CommD	D3 400 + Ca 500 mg vs. nil	Grip and lower limb strength, TUAG, MCT	NR	No effect
Kenny et al. (387)	65	M	76	Negative	6 months	26 (65)	CommD	D3 1000 + Ca 500 mg vs. nil	Grip and leg strength, PAS, supine TST, TUAG, 6-ft. walk, balance	NR	No effect
Corless et al. (292)	63	M, F	82	Negative	40 wk	17.2 (43)	Hosp	D2 9000 vs. nil	ADL score with walking up stairs and on flat	NR	No effect
Moreira-Pfrimer et al. (285)	56	M, F	>60	Positive	6 months	40–46 (100–115)	Frail, LSGC	Ca 1000 + D3 150,000 by 2 + 90,000/month by 4 vs. Ca + placebo	Hip flexor and knee extensor strength	NR	Both improved
Songpatanasilp et al. (288)	42	F	>65	Positive	12 wk	<30 (75)		1α−OHD3 (0.5 μg) + Ca 1500 mg vs. Ca/Placebo	Quadriceps strength	Baseline strength	Improved quadriceps strength
Gupta et al. (388)	40	M, F	32	Positive	6 months	8–10 (21–25)	Asian	Ca 1000 mg + D3 60,000/wk, 12 doses	Grip and calf strength, respiratory pressures, 6-min walk, MRS	Age, sex, basal measures	Improved grip and calf strength and 6-min walk
Gloth et al. (389)	32	M, F	>65	Positive, post hoc subgroup	6 months	<15 (37.5)	Frail, CommD, NH	Ca (no dose) + D2 400 or Ca + D2 100,000/3 months or Ca alone	FEFA score	NR	Subgroup increase 25D >3 ng/ml D improved

Study (Ref.)	n	Sex	Age (yr)	Positive or negative	Duration	Basal 25D [ng/ml (nmol/liter)]	Other	Vitamin D and Ca/other	Outcomes	Adjustments	Main results
Brunner et al. (383)	33,067	F	50–79	Negative	7 yr	NR	WHI study	D3 400 + Ca 1000 mg vs. placebo	Grip, 6-m walk, chair-STS, exercise	Age, WHI group	No improvement
Zhu et al. (286)	302	F	70–90	Positive, post hoc subgroup	1 yr	18 (44)	CommD	D2 1000 + Ca 1000 or Ca alone	Ankle, knee, hip strength, TUAG	NR	Lowest basal tertile ↑ hip and TUAG
Latham et al. (291)	243	M, F	80	Negative	6 months	17 (42)	Adverse outcomes, frail	D3 300,000 by 1 + exercise vs. placebo	Knee strength, balance, TUAG, 4-m walk, falls	NR	Higher rates of injury with intervention
Lips et al. (384)	226	M, F	>70	Positive, one measure	16 wk	6–20 (15–50)	Ambulatory	D3 8400/wk vs. placebo	Body sway, PAS	Basal sway and 25D	Subgroup ↑ basal sway improved
Kukuljan et al. (293)	180	M	50–79	Negative	18 months	34 (86)	CommD	Milk + D3 800 + Ca 1000 mg vs. placebo ± exercise	Sway, step test, lateral pulldown, leg and bench press	NR	No effect
El-Hajj et al. (295)	179	F	10–17	Positive, one measure	1 yr	14 (35)	School	D3 1400 vs. D3 14,000/wk vs. placebo	Grip, lean mass	NR	No effect
Dhesi et al. (284)	139	M, F	≥65	Positive, three measures	6 months	≥12 (30)	Falls	D2 600,000 im once vs. placebo	CRT, AFPT, quadriceps strength, falls	NR	AFPT, CRT, and sway improved
Johnson et al. (385)	109	M, F	>60	Negative	6 months	NR	CommD	D 2000 vs. placebo	Muscle function in arm and leg	NR	No effect
Witham et al. (386)	105	M, F	>70	Negative	20 wk	<20 (50)	CF	D3 100,000, by 2 or placebo	6-min walk, QOL, activity, function	NR	No effect
Grady et al. (294)	98	M, F	>69	Negative	6 months	24 (60)	Ambulatory	1,25D 0.5 μg or placebo	Quads, grip strength	Age, sex, CrCl, strength	No effect
Bunout et al. (283)	96	M, F	>70	Positive, one measure	9 months	12 (30)	Ambulatory	D3 400 + Ca 800 mg vs. Ca alone	Quads, TUAG, walk speed, other	Compliance	Walk speed increased
Glerup et al. (208)	77	F	32–36	Positive	3–6 months	A (n = 55), 7 (17); D, 42 (104)		D2 100,000 im by 6 + 4–600/d + Ca 8–1200 vs. nil in Danes	Knee extensors	NR	Arabic women improved
Ward et al. (287)	73	F	41–74	Positive, one measure	1 yr	<15 (37.5)	School	Four doses of D2 150,000	Jumping, grip, weight, muscle strength	NR	Jump efficiency improved
Janssen et al. (289)	70	F	>65	Negative, baseline correlated	6 months	8–20 (20–50)	CommD	D3 400 + Ca 500 mg vs. nil	Grip and lower limb strength, TUAG, MCT	NR	No effect
Kenny et al. (387)	65	M	76	Negative	6 months	26 (65)	CommD	D3 1000 + Ca 500 mg vs. nil	Grip and leg strength, PAS, supine TST, TUAG, 6-ft. walk, balance	NR	No effect
Corless et al. (292)	63	M, F	82	Negative	40 wk	17.2 (43)	Hosp	D2 9000 vs. nil	ADL score with walking up stairs and on flat	NR	No effect
Moreira-Pfrimer et al. (285)	56	M, F	>60	Positive	6 months	40–46 (100–115)	Frail, LSGC	Ca 1000 + D3 150,000 by 2 + 90,000/month by 4 vs. Ca + placebo	Hip flexor and knee extensor strength	NR	Both improved
Songpatanasilp et al. (288)	42	F	>65	Positive	12 wk	<30 (75)		1α−OHD3 (0.5 μg) + Ca 1500 mg vs. Ca/Placebo	Quadriceps strength	Baseline strength	Improved quadriceps strength
Gupta et al. (388)	40	M, F	32	Positive	6 months	8–10 (21–25)	Asian	Ca 1000 mg + D3 60,000/wk, 12 doses	Grip and calf strength, respiratory pressures, 6-min walk, MRS	Age, sex, basal measures	Improved grip and calf strength and 6-min walk
Gloth et al. (389)	32	M, F	>65	Positive, post hoc subgroup	6 months	<15 (37.5)	Frail, CommD, NH	Ca (no dose) + D2 400 or Ca + D2 100,000/3 months or Ca alone	FEFA score	NR	Subgroup increase 25D >3 ng/ml D improved

Doses for vitamin D and calcium are daily and administered orally (unless stated otherwise). A, Arab women; AFPT, aggregate functional performance time; CF, cardiac failure; CrCl, creatinine clearance; CRT, choice reaction time; CommD, community dwelling; D, Danish women; FEFA, frail elderly functional assessment score; Hosp, in hospital; ITT, intention-to-treat analysis; LSGC, long-stay geriatric care units; MCT, modified Cooper test; MRS, magnetic resonance spectroscopy; Quads, quadriceps strength; PAS, physical activity/performance score; TST, to stand test; WHI, Women's Health Initiative.

A two by two randomized study of patients treated with calcium 800 mg with or without resistance training, with or without vitamin D 400 IU daily for 9 months found that vitamin D improved physical performance (283). Quadriceps strength, physical performance test, and TUAG were significantly improved by vitamin D and by resistance training, with an additive benefit in the group that received both (283).

In a study of 139 ambulatory older subjects with a history of falls and vitamin D deficiency [25D <12 ng/ml (30 nmol/liter)], treatment with vitamin D₂ (600,000 IU im) had a significant effect on aggregate functional performance time but no effect on either falls or quadriceps strength at 6 months follow-up vs. placebo (284).

Among 56 institutionalized persons over 60 yr of age, those randomized to receive calcium and vitamin D (two doses of 150,000 IU then 90,000 IU monthly) demonstrated significant improvements in maximal isometric strength of hip flexors and knee extensors after 6 months (285). Subgroup analysis demonstrated greater improvements in muscle function among subjects with lower baseline 25D levels [<20 ng/ml (50 nmol/liter)].

Similarly, among 302 older, community-dwelling women, those in the lowest tertile of 25D levels who received daily calcium (1000 mg) and vitamin D₂ (1000 IU) displayed the most pronounced improvements in lower limb muscle function over 1 yr as opposed to those on calcium alone (286).

Among 69 postmenarcheal adolescent females, those randomized to receive 150,000 IU vitamin D₂ orally every 3 months for 1 yr demonstrated significant improvements in movement efficiency, a composite of jump height and velocity measured by mechanography, compared with baseline (287). Additionally, at baseline, higher 25D levels correlated with greater jumping velocity.

In a short study of 42 postmenopausal women, 12 wk treatment with 1α-OHD₃ (0.5 μg) and calcium led to significant improvements in quadriceps strength compared with those receiving calcium alone (288).

4. Muscle strength and function: negative studies

In a study of 70 vitamin D-deficient women [25D = 8–20 ng/ml (20–50 nmol/liter)], 6 months of vitamin D and calcium (400 IU and 500 mg) had no effect on grip or knee strength vs. calcium alone. Baseline 25D levels showed an inverse correlation with these parameters of muscle function (289).

In a study of 686 community-dwelling women over 70 yr, treatment with oral vitamin D₃ (150,000 IU every 3 months) for a 9-month period had no significant effect on falls or hand grip strength compared with placebo (290). However, a randomly selected subgroup of 40 participants had a mean baseline 25D of 26 ng/ml (66 nmol/liter), suggesting that the group at large were vitamin D sufficient.

Other studies have failed to demonstrate improvements in muscle strength after vitamin D supplementation, regardless of baseline vitamin D status (291–295), as summarized in Table 7. A multicenter study of 243 frail, older patients reported no difference in parameters of physical performance between those randomized to receive a single dose of 300,000 IU of vitamin D vs. placebo (291). There was no effect in the subset with low baseline 25D levels [<12 ng/ml (30 nmol/liter)] despite significant improvements in 25D levels. Some studies have examined other forms of vitamin D, namely 1,25D and 1α-OHD₃, with variable effects. Among 98 older subjects with mild renal impairment, 1,25D (0.5 μg daily) resulted in no improvement over a 6-month period vs. placebo, and some subjects on 1,25D developed hypercalciuria and required dose reduction (294).

One negative study examined 179 vitamin D-deficient adolescent females in Lebanon. Those randomized to receive vitamin D₃ (doses of 1,400 or 14,000 IU/wk) did not demonstrate improved grip strength but did have greater increases in lean mass, bone area, and total hip bone mineral content vs. placebo after 1 yr (295).

Two studies have examined the effects of combining vitamin D supplementation with high-resistance training on muscle strength in older individuals (283, 293). In one study of 180 community-dwelling males (50–79 yr), those randomized to receive an intensive program of resistance training three times per week demonstrated improvements in strength. Those randomized to receive fortified milk alone (containing vitamin D 800 IU, calcium 1000 mg, and protein 13.2 g daily) demonstrated no additional improvements (293). Those receiving high-resistance training with vitamin D (400 IU) and calcium (800 mg) over a 9-month period showed improvements in TUAG but not in quadriceps strength compared with those who received resistance training and calcium (283).

5. Meta-analyses of muscle function

In one meta-analysis, the substantial variability in the parameters of muscle function among studies, use of measures without established validity or reliability, and lack of blinded outcome assessments were cited as reasons for inability to pool data (30).

On assessing 17 RCT involving 5072 participants, there was no significant effect of vitamin D supplementation on grip strength or proximal lower limb strength in adults with 25D levels over 10 ng/ml (25 nmol/liter) at baseline (24). However, for adults with deficiency [25D <10 ng/ml (25 nmol/liter)], a beneficial effect on hip muscle strength was found.

In another meta-analysis of 16 RCT, in which baseline 25D levels were below 20 ng/ml (50 nmol/liter) in 11 studies, the authors noted the publication of a greater number of studies that showed no effect rather than a beneficial effect of vitamin D supplementation on muscle function and that there were no obvious characteristics to differentiate studies with positive and negative findings (296).

In a more recent meta-analysis of 13 RCT involving elderly subjects who were predominantly vitamin D deficient or insufficient, vitamin D supplementation with 800–1000 IU daily was associated with improvements in lower extremity strength and balance (297). The meta-analysis included only randomized trials of older individuals in whom baseline and posttreatment parameters of muscle function were assessed. Trials in younger individuals (295) or those that included muscle training as part of the treatment were not included (293). This meta-analysis found no effect on gait.

6. Summary: vitamin D, muscle strength, and physical performance

Although some data suggest a beneficial effect of vitamin D supplementation on muscle function, particularly in vulnerable populations and those with low baseline vitamin D levels (208, 286), the evidence base is limited by highly heterogeneous studies that assess muscle function by different methods. Hence, larger studies that use standardized, reproducible assessments of muscle strength and double-blinded treatment regimens are necessary to clarify this important issue and guide recommendations. Such studies should ideally consider baseline vitamin D status and confirm adequate replacement is achieved by a rise in 25D to the normal range.

G. Muscle morphology and electromyography (EMG)

Several reports, dating back to the 1970s, have characterized the morphological appearance of skeletal muscle among vitamin D-deficient subjects and thus provided some evidence in support of a direct role for vitamin D in the morphology and development of muscle.

1. Open-label studies

In 1974, a case series of 13 patients with various degrees of proximal myopathy in the context of chronic renal failure was described (203). Ten of the 13 patients displayed significantly shorter mean action potential durations of the deltoid and quadriceps muscles on EMG. They also displayed moderate atrophy of type II (i.e. fast twitch) muscle fibers on the basis of myofibrillar ATPase staining and degenerative changes on electron microscopy with small foci of fiber necrosis, lytic vacuoles, and Z-band degeneration in four patients. Although vitamin D levels were not determined, because this was before the era of the standardized assay, substantial improvement in muscle strength after im vitamin D treatment in a proportion of the patients was reported. In another series of four uremic patients, the finding of type II muscle fiber atrophy was linked to vitamin D deficiency on the basis of significantly elevated PTH levels (298).

In 1975, gluteal muscle biopsies of 12 patients with laboratory evidence of osteomalacia displayed nonspecific muscle fiber atrophy (299). A distinction was made between patients with isolated nutritional deficiency in whom biopsy changes were mild compared with those with an additional condition including hyperparathyroidism, hyperthyroidism, or uremia who also demonstrated myofibrillar degeneration and infiltration with amorphous material.

One year later, Irani (201) reported a case series of 15 women with nutritional osteomalacia who demonstrated significantly shorter motor unit action potentials and a greater proportion of polyphasic potentials on EMG compared with controls. Muscle biopsies from those with osteomalacia demonstrated nonspecific muscle fiber atrophy. Complete resolution in EMG changes after a 5-wk course of high-dose vitamin D supplementation (600,000 IU of vitamin D₂ weekly or fortnightly) was noted in the three patients who were retested. In 1979, two patients with osteomalacia demonstrated type II muscle fiber atrophy in addition to scattered necrosis and derangement of the intermyofibrillar network on muscle biopsy (300).

Eleven patients with a condition described as bone loss of aging had muscle biopsies from the vastus lateralis before and after treatment with 1α-OHD₃ and calcium for 3–6 months (301). The predominant finding was an increase in the proportion and cross-sectional size of fast-twitch type IIa fibers. Measures of the oxidative capacity of muscle, succinate dehydrogenase, and total phosphorylase activity were low at baseline and increased with treatment. Lactate dehydrogenase activity, a measure of anaerobic metabolism, did not change. Interestingly, the proportion of type IIb fibers (very-fast-twitch fibers) decreased significantly with treatment. This was the first report to demonstrate changes in muscle morphology and oxidative capacity after treatment of presumably vitamin D-deficient subjects with a vitamin D analog.

Three years later, Young et al. (302) confirmed these findings by demonstrating significant increases in the proportion of type II muscle fibers in biopsies of the vastus lateralis muscle after 3 months of vitamin D supplementation among 12 patients with osteomalacia. In association with these findings, quadriceps muscle strength also improved significantly using an isodynamic dynamometer. However, this body of evidence dating back to the 1970s may be confounded by the many biochemical abnormalities associated with renal failure and osteomalacia such as hyperparathyroidism and disturbances in calcium and phosphate levels. These provide indirect mechanisms that may independently alter muscle function (Fig. 4). Nevertheless, the changes in muscle morphology and performance after vitamin D supplementation in these subjects are important preliminary observations.

Recent studies have reported an association between significantly higher skeletal muscle fat content and vitamin D deficiency. In one study of 90 postpubertal females in California, the proportion of muscle fat, assessed by comparing the attenuation signal of a 2-cm² section of the rectus femoris with the adjacent sc fat on computed tomography, was found to strongly correlate in an inverse fashion with serum 25D levels (303). This was independent of body mass or computed tomography measures of sc and visceral fat. The percentage of muscle fat was significantly lower in women with normal vs. subnormal serum 25D levels.

In another study of 366 older patients receiving magnetic resonance imaging (MRI) of one shoulder for the investigation of potential rotator cuff injury, a correlation between higher fatty infiltration of rotator cuff muscles and lower serum levels of 25D was reported (304). After multivariate linear regression analysis, this association remained statistically significant in two muscle groups (i.e. supraspinatus and infraspinatus muscles) but only among those whose MRI also demonstrated a full-thickness rotator cuff tear (228 patients).

A third study using MRI of the thigh in 20 older subjects also reported an inverse correlation between muscular fatty degeneration and 25D (305). Interestingly, selective and near-total fatty degeneration of at least one muscle was observed among 11 vitamin D-deficient patients [25D <20 ng/ml (50 nmol/liter)].

A recent cross-sectional study demonstrated a positive correlation between 1,25D levels and total skeletal muscle mass as measured on DEXA among subjects younger than 65 yr (306). This was supported by greater isometric knee extension moment in women with higher 1,25D levels. However, no association was found between 25D levels and muscle mass or strength or in those over 65 yr of age. Among 26 subjects with chronic kidney disease, thigh muscle cross-sectional area on MRI correlated significantly with a model including 1,25D levels, calcium levels, and daily physical activity (307). Functional parameters assessing gait and proximal musculature also independently correlated with 1,25D.

Although a majority of highly trained adolescent male ballet dancers had low vitamin D levels [25D <20 ng/ml (50 nmol/liter) in nine of 16 study participants], there was no correlation between 25D, body composition on DEXA, or reports of muscle injury in this study (308).

2. EMG and muscle biopsies: randomized study

A study that randomized 96 elderly women with poststroke hemiplegia and severe vitamin D deficiency [<10 ng/ml (25 nmol/liter)] to vitamin D₂ (1000 IU daily) or placebo for 2 yr reported significant and dramatic increases in the proportion and diameter of type II muscle fibers (85). These parameters deteriorated significantly in the placebo group.

3. EMG and muscle biopsies: summary

In summary, it appears that vitamin D deficiency results in significant and reversible changes in EMG and type II muscle fiber atrophy, the latter being an independent predictor for falls in one study (85). However, the changes are nonspecific, being similar to those seen in other conditions. Although fatty infiltration in skeletal muscle has been suggested by three recent studies, these are cross-sectional and based on imaging modalities that may not be validated for the assessment of muscle fat. Muscle becomes fatty with disuse, and thus this measure may be confounded by decreased exercise associated with both increased muscle lipid and lower vitamin D. These modalities are not equipped to identify intracellular fat, perhaps of greater pathophysiological significance.

H. Insulin sensitivity and glucose handling

A broad range of epidemiological and randomized clinical studies together with specific research on molecular pathways and animal models have drawn links between vitamin D and insulin sensitivity. This is relevant to the topic of vitamin D and muscle because under normal physiological conditions, skeletal muscle is responsible for approximately 85% of whole-body insulin-mediated glucose uptake (102).

Insulin resistance, a highly prevalent condition that contributes to the pathogenesis of type 2 diabetes, is primarily due to defective insulin-stimulated glucose uptake in skeletal muscle resulting from the production of various inflammatory mediators, adipokines, and FFA by adipocytes in predominantly overnourished and obese individuals (309). However, in recognizing the complex processes involved in insulin resistance, a number of reversible factors with potential etiological relevance to this condition are being considered. One of these factors is vitamin D deficiency. In this section, we will review human clinical studies that examine the association between vitamin D status and insulin sensitivity.

1. Cross-sectional studies: vitamin D and insulin sensitivity

Studies have examined the association between parameters of insulin resistance and vitamin D status in nondiabetic individuals. In one report, 25D was inversely correlated with the homeostasis model assessment of insulin resistance (HOMA-IR) among 214 Arab-American men, but no such association was found among the 317 women of the same ethnicity included in this study (310). Among 808 nondiabetic participants of the Framingham Offspring Study, plasma 25D concentrations were inversely associated with fasting insulin concentrations and HOMA-IR after adjustment for age, sex, and BMI (311). A similar association between 25D levels and HOMA-IR was found in a group of 712 subjects at risk of diabetes (312).

Among 1941 adolescents who participated in the National Health and Nutrition Examination Survey from 2001–2006, adjusted concentrations of insulin were significantly higher among male subjects who were vitamin D deficient [<20 ng/ml (50 nmol/liter)] compared with those with higher vitamin D levels [≥30 ng/ml (75 nmol/liter)], suggesting a potential role vitamin D status in insulin sensitivity (313).

However, a recent study that employed the gold-standard technique in the assessment of insulin sensitivity, namely the hyperinsulinemic-euglycemic clamp, found that the association between insulin sensitivity in 39 nondiabetic subjects and 25D levels become nonsignificant after adjustment for other factors including BMI (314). Similarly, among 381 nondiabetic university students in Lebanon and 510 nondiabetic subjects from a largely obese ethnic minority in Canada (i.e. Canadian Cree), the inverse association between 25D levels and HOMA-IR also became nonsignificant after adjustment for BMI in addition to other factors (315, 316). In another study of 126 healthy young adults, there was a significant association between 25D levels and insulin sensitivity on a hyperglycemic clamp study that remained after adjustment for a range of factors (317).

Therefore, it is clear that the inverse correlation between 25D and BMI, as reported in a number of studies (314, 318), may particularly confound the assessment of these observational data. In fact, a recent study suggests that it may be more accurate to consider adiposity rather than BMI per se as the particular confounding factor (319). In a study of 1882 nondiabetic individuals, it was the inclusion of a computed tomography measure of visceral adiposity rather than BMI and waist circumference in the multivariate analysis that caused the inverse association between vitamin D status and markers of insulin resistance, namely HOMA-IR and log insulin levels, to be insignificant (319).

Several mechanisms associating vitamin D deficiency with obesity have been proposed, including the great capacity of adipose tissue to store vitamin D (80, 320) and the avoidance of sunlight exposure and outdoor activity among potentially self-conscious, obese individuals (320). In confirmation of the former mechanism, a study of 116 obese women reported that fat mass measured by isotope dilution method was a strong predictor of serum 25D levels both 5 yr before and 10 yr after bilio-pancreatic diversion surgery and that vitamin D levels did not correlate with insulin sensitivity at either time on the basis of the euglycemic-hyperinsulinemic clamp studies (321).

The impact of PTH, which has an inverse relation to vitamin D status and is also associated with diabetes (322), has been addressed in a small number of studies. A study including 15 subjects with secondary hyperparathyroidism (serum PTH >6.4 pmol/liter) and 15 controls found that after adjustment for BMI, age, and sex, serum 25D levels were significantly associated with the insulin sensitivity index on a 3-h hyperglycemic clamp, but PTH levels were not (323). Similarly, a significant adjusted association between 25D and fasting insulin was reported in a study of 654 adult subjects from Canada, but PTH was not associated with this parameter after multivariate adjustment (324).

Apart from insulin resistance of skeletal muscle, the pathophysiology of type 2 diabetes comprises a range of other factors. Vitamin D may play a role in these other processes with cross-sectional studies and meta-analyses reporting an association between vitamin D deficiency/insufficiency and the incidence of diabetes in various populations (325–328). However, not all studies confirm this observation, and there is substantial heterogeneity between studies in their design and adjustment for confounders (329–331).

2. Prospective studies: vitamin D and insulin sensitivity

Observational studies have examined the relationship between 25D and the prospective risk of developing insulin resistance.

In the prospective Ely study (1990–2000), baseline 25D levels of 524 nondiabetic men and women were inversely associated with the 10-yr risk of insulin resistance, on the basis of HOMA-IR and fasting insulin after adjustment for a range of factors including age, sex, BMI, and calcium and PTH levels (332). Each 10-ng/ml (25 nmol/liter) increase in baseline 25D was associated with a significant decrease in HOMA-IR score (i.e. 0.16 U) at 10 yr.

In a recent study that assessed 5200 participants of the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study, lower baseline 25D levels were associated with a higher risk of developing diabetes over the 5-yr follow-up period (333). After adjustment for a range of factors, the authors reported that each 10-ng/ml (25 nmol/liter) increment in serum 25D was associated with a 24% reduced 5-yr risk of diabetes. Regarding insulin resistance, a positive and independent association with HOMA-IR at 5 yr was also reported. In contrast to an earlier report (334), no association between dietary calcium intake and diabetes risk or the follow-up homeostasis model assessment of insulin sensitivity score was found (333).

Apart from insulin resistance, a number of studies have also reported an association between baseline 25D levels and the long-term risk of diabetes (334–336). However, not all such studies have supported this association (337–339).

3. Interventional studies: vitamin D and insulin sensitivity

Mixed results have emerged from a number of interventional studies that have sought to address the impact of vitamin D supplementation on glucose homeostasis and parameters of insulin sensitivity.

There was no difference in parameters of glucose homeostasis among 238 postmenopausal women who were randomized to receive 2 yr of treatment with vitamin D₃ (2000 IU daily) or lα-OHD₃ (0.25 μg daily) or 1 yr of treatment with 1,25D (0.25–0.50 μg) daily vs. placebo (340). Similarly, no differences in insulin-mediated glucose uptake on the euglycemic clamp study were found in 18 healthy males randomized to receive either 1,25D 1.5 μg daily or placebo; however, treatment in this study was only 7 d (341).

Studies examining subjects at risk of diabetes have suggested improvements in glucose homeostasis with vitamin D supplementation. In three studies, significant improvements were reported in insulin sensitivity, insulin secretion, and/or the disposition index in subjects at risk of diabetes who were randomized to receive supplemental vitamin D₃ and calcium (2000 IU and 500 mg, respectively) vs. calcium alone for 16 wk, high-dose vitamin D₃ (120,000 IU) every 2 wk vs. placebo for 6 wk, and vitamin D₃ and calcium (700 IU and 500 mg daily, respectively) vs. placebo for 3 yr (342–344).

A double-blind randomized trial of 81 South Asian women living in New Zealand who were found to be both insulin resistant on HOMA-IR and vitamin D deficient [25D <20 ng/ml (50 nmol/liter)] reported significant reductions in insulin resistance and fasting insulin levels among those randomized to receive vitamin D₃ (4000 IU daily) vs. placebo for 6 months (345).

In a recent randomized trial including 90 diabetic subjects, those randomized to receive vitamin D-fortified yogurt twice daily (each containing 500 IU) or vitamin D- and calcium-fortified yogurt demonstrated improved glycemic control on glycated hemoglobin (HbA1c) and improved insulin resistance on HOMA-IR compared with those receiving plain yogurt for 12 wk (346). Importantly, an inverse correlation was observed between changes in serum 25D and HOMA-IR in this study.

In another study, 10 females with type 2 diabetes who were predominantly vitamin D deficient reported a significant reduction in a marker of peripheral insulin resistance after 1 month of vitamin D₃ supplementation (1332 IU daily) (347). However, this study had no control group.

Conversely, a number of small studies have failed to demonstrate any benefits in association with vitamin D supplementation in patients with type 2 diabetes. In 20 diabetic subjects, a randomized trial reported no improvements in fasting or stimulated glucose, insulin, C-peptide, or glucagon concentrations among those receiving 1,25D (1 μg daily) for 4 d vs. placebo (348). Among 28 Asian Indian patients with type 2 diabetes, those randomized to receive vitamin D supplementation for 4 wk did not demonstrate a significant difference in markers of insulin resistance (i.e. fasting insulin, post-oral glucose tolerance test serum insulin levels, and HOMA-IR) compared with those receiving placebo (349). Similarly, in 32 diabetic subjects, 6 months of supplemental vitamin D (40,000 IU/wk) had no effect on fasting insulin, C-peptide, or HbA1c levels compared with baseline or those receiving placebo (350). It is probably reasonable to conclude that these studies were underpowered to answer the question in either direction.

In one case series of three British Asians with diabetes and vitamin D deficiency [25D <6 ng/ml (15 nmol/liter)], high-dose vitamin D supplementation (300,000 IU im) was associated with subsequent deterioration in glycemic control on HbA1c and progression of insulin resistance on fasting insulin resistance index (351).

Recent post hoc analyses of eight trials including participants with normal glucose tolerance at baseline and three small trials of patients with established type 2 diabetes demonstrated no effect of vitamin D supplementation on glycemic outcomes (352). However, two trials examining patients with baseline glucose intolerance reported improvements in insulin resistance among those receiving vitamin D supplementation (349, 350).

4. Summary: vitamin D and insulin sensitivity

Substantial differences in study design, duration, and type of vitamin D supplementation and the particular populations studied in these trials make collective assessment of these results difficult. Although some large trials suggest a beneficial effect of vitamin D supplementation in the reduction of insulin resistance, others do not. Furthermore, to ascertain whether the potential glycemic benefits of supplemental vitamin D are more pronounced in those with vitamin D deficiency or poor glycemic control at baseline, larger trials of longer duration are necessary. More than 20 trials are currently under way to address this question (www.clinicaltrials.gov).

VII. Conclusions

See Table 8 for conclusions.

Table 8.

Conclusions and outstanding questions

Conclusions

Vitamin D exerts rapid and genomic effects in primary muscle cells and cell lines. These effects relate to intracellular calcium handling, differentiation and contractile protein composition.

In vivo, it is not clear whether VDR is expressed in adult skeletal muscle.

Whole-body VDRKO mice and vitamin D-deficient animals display significant defects in muscle function and development.

In humans, single nucleotide polymorphisms in the gene encoding VDR have been associated with differences in muscle strength.

Changes in muscle morphology in humans with severe vitamin D deficiency have been reported since the 1970's.

Proximal myopathy and muscle pain in subjects with severe vitamin D deficiency resolve following vitamin D supplementation.

Associations between vitamin D deficiency, muscle weakness and falls are confounded by factors including frailty and lower exposure to sunlight. Clinical parameters of muscle function are not standardized making data aggregation difficult.

Randomized data suggest that vitamin D supplementation may reduce falls in older individuals but not all studies support this conclusion.

The recommended dose of vitamin D supplementation and vitamin D targets remain hotly contested issues.

Outstanding questions

Does the VDR exist in fully differentiated adult muscle and does it have physiological relevance at this site? Or rather, as suggested by in vitro studies, is its role predominantly related to the function of immature muscle cells such as in myogenesis?

Are changes in muscle function and morphology directly related to vitamin D or indirectly to its effects in calcium and mineral homeostasis?

Does skeletal muscle possess the ability to 1-α-hydroxylate 25D at any stage in its development?

As suggested by studies on phosphate handling in myocytes, does 25D itself exert direct effects on muscle?

Is vitamin D deficiency or its reversal an important consideration among those with other muscle disorders such as congenital dystrophies and acquired immune-related myositis?

Conclusions

Vitamin D exerts rapid and genomic effects in primary muscle cells and cell lines. These effects relate to intracellular calcium handling, differentiation and contractile protein composition.

In vivo, it is not clear whether VDR is expressed in adult skeletal muscle.

Whole-body VDRKO mice and vitamin D-deficient animals display significant defects in muscle function and development.

In humans, single nucleotide polymorphisms in the gene encoding VDR have been associated with differences in muscle strength.

Changes in muscle morphology in humans with severe vitamin D deficiency have been reported since the 1970's.

Proximal myopathy and muscle pain in subjects with severe vitamin D deficiency resolve following vitamin D supplementation.

Associations between vitamin D deficiency, muscle weakness and falls are confounded by factors including frailty and lower exposure to sunlight. Clinical parameters of muscle function are not standardized making data aggregation difficult.

Randomized data suggest that vitamin D supplementation may reduce falls in older individuals but not all studies support this conclusion.

The recommended dose of vitamin D supplementation and vitamin D targets remain hotly contested issues.

Outstanding questions

Does the VDR exist in fully differentiated adult muscle and does it have physiological relevance at this site? Or rather, as suggested by in vitro studies, is its role predominantly related to the function of immature muscle cells such as in myogenesis?

Are changes in muscle function and morphology directly related to vitamin D or indirectly to its effects in calcium and mineral homeostasis?

Does skeletal muscle possess the ability to 1-α-hydroxylate 25D at any stage in its development?

As suggested by studies on phosphate handling in myocytes, does 25D itself exert direct effects on muscle?

Is vitamin D deficiency or its reversal an important consideration among those with other muscle disorders such as congenital dystrophies and acquired immune-related myositis?

Table 8.

Conclusions and outstanding questions

Conclusions

Vitamin D exerts rapid and genomic effects in primary muscle cells and cell lines. These effects relate to intracellular calcium handling, differentiation and contractile protein composition.

In vivo, it is not clear whether VDR is expressed in adult skeletal muscle.

Whole-body VDRKO mice and vitamin D-deficient animals display significant defects in muscle function and development.

In humans, single nucleotide polymorphisms in the gene encoding VDR have been associated with differences in muscle strength.

Changes in muscle morphology in humans with severe vitamin D deficiency have been reported since the 1970's.

Proximal myopathy and muscle pain in subjects with severe vitamin D deficiency resolve following vitamin D supplementation.

Associations between vitamin D deficiency, muscle weakness and falls are confounded by factors including frailty and lower exposure to sunlight. Clinical parameters of muscle function are not standardized making data aggregation difficult.

Randomized data suggest that vitamin D supplementation may reduce falls in older individuals but not all studies support this conclusion.

The recommended dose of vitamin D supplementation and vitamin D targets remain hotly contested issues.

Outstanding questions

Does the VDR exist in fully differentiated adult muscle and does it have physiological relevance at this site? Or rather, as suggested by in vitro studies, is its role predominantly related to the function of immature muscle cells such as in myogenesis?

Are changes in muscle function and morphology directly related to vitamin D or indirectly to its effects in calcium and mineral homeostasis?

Does skeletal muscle possess the ability to 1-α-hydroxylate 25D at any stage in its development?

As suggested by studies on phosphate handling in myocytes, does 25D itself exert direct effects on muscle?

Is vitamin D deficiency or its reversal an important consideration among those with other muscle disorders such as congenital dystrophies and acquired immune-related myositis?

Conclusions

Vitamin D exerts rapid and genomic effects in primary muscle cells and cell lines. These effects relate to intracellular calcium handling, differentiation and contractile protein composition.

In vivo, it is not clear whether VDR is expressed in adult skeletal muscle.

Whole-body VDRKO mice and vitamin D-deficient animals display significant defects in muscle function and development.

In humans, single nucleotide polymorphisms in the gene encoding VDR have been associated with differences in muscle strength.

Changes in muscle morphology in humans with severe vitamin D deficiency have been reported since the 1970's.

Proximal myopathy and muscle pain in subjects with severe vitamin D deficiency resolve following vitamin D supplementation.

Associations between vitamin D deficiency, muscle weakness and falls are confounded by factors including frailty and lower exposure to sunlight. Clinical parameters of muscle function are not standardized making data aggregation difficult.

Randomized data suggest that vitamin D supplementation may reduce falls in older individuals but not all studies support this conclusion.

The recommended dose of vitamin D supplementation and vitamin D targets remain hotly contested issues.

Outstanding questions

Does the VDR exist in fully differentiated adult muscle and does it have physiological relevance at this site? Or rather, as suggested by in vitro studies, is its role predominantly related to the function of immature muscle cells such as in myogenesis?

Are changes in muscle function and morphology directly related to vitamin D or indirectly to its effects in calcium and mineral homeostasis?

Does skeletal muscle possess the ability to 1-α-hydroxylate 25D at any stage in its development?

As suggested by studies on phosphate handling in myocytes, does 25D itself exert direct effects on muscle?

Is vitamin D deficiency or its reversal an important consideration among those with other muscle disorders such as congenital dystrophies and acquired immune-related myositis?

In his 1922 publication on the cure of rickets by sunlight, Alfred Hess (35) remarked that "although we have realized the importance of light in the growth of plant life, we have [until now] accorded it too little significance in the development of animal life." Since that time, we have come a long way in recognizing the role of UV radiation in the photochemical synthesis of vitamin D, the role of vitamin D in calcium and mineral homeostasis, and the similarity of 1,25D to members of the steroid family with their cholesterol precursor, carbon-ringed structures, and ability to bind to specific nuclear receptors in the genomic mediation of developmental and functional effects.

Although steroid hormones are known to exert diverse effects in multiple organs and tissues, a role for vitamin D beyond its predominant effects on bone and mineral homeostasis has been hotly contested. Muscle stands at the frontier of the emerging concept of vitamin D's extraskeletal role because it shares its ancestral origin with bone in the common mesenchymal stem cell and relies heavily on intracellular calcium handling for contraction, insulin sensitivity, and cellular plasticity (99).

In this review, we have adopted a multilayered approach in examining evidence from human clinical studies as well as reports on animal and cell models to piece together the current knowledge of vitamin D's effects in skeletal muscle. The broad evidence base is generally in favor of a role for vitamin D in the development and function of skeletal muscle.

The strongest evidence comes from studies that report distinct morphological changes in the muscle of vitamin D-deficient subjects, others that describe significant impairments in the muscle function of VDRKO mice, and molecular studies that have mapped out the various intracellular responses of cultured muscle cells to vitamin D (129, 173, 174). As a result, we have come closer to answering the perennial question as to whether vitamin D's influence on muscle is direct or indirect, and the answer appears to be both.

Outstanding questions remain, including the precise role of vitamin D in muscle differentiation, the possibility of specific biological activity of 25D in muscle, and the current controversy regarding the in vivo presence of the VDR in muscle tissue.

In the clinical domain, observations of reversible myopathy in subjects with severe vitamin D deficiency have been reported for some time. Cross-sectional data reporting a high prevalence of vitamin D deficiency among subjects with falls, muscle weakness, and insulin resistance are also present (211, 274, 327). However, confounding variables are a caveat in the interpretation of this circumstantial evidence. Furthermore, the demonstration of unequivocal improvements in muscle function among subjects with mild to moderate degrees of vitamin D deficiency randomized to receive vitamin D supplementation has been elusive. Possible reasons for this include heterogeneity in study design and supplemental regimens and the general lack of large-scale trials to address this issue. These challenges and others remain to be addressed.

There is reasonable evidence from cellular, animal, and at least some human studies that muscle responds to vitamin D. Although molecular pathways by which vitamin D acts on the myocyte have been identified, there is scope for more clarification. Studies are also needed to clarify the therapeutic potential of vitamin D in the treatment of age-related sarcopenia and perhaps other myopathies. In the meantime, it would be prudent for clinicians to seek and manage vitamin D deficiency in individuals at risk of these conditions.

Acknowledgments

The authors gratefully acknowledge Professor John Eisman (Garvan Institute of Medical Research, Sydney, Australia) for reviewing the manuscript.

Disclosure Summary: C.M.G. received salary support from a postgraduate scholar award from University of Sydney. J.E.G. received funding from the Diabetes Australia Research Trust and the National Health and Medical Research Council. The remaining authors have no conflicts of interest to report.

Abbreviations

• AA

• AC

• BMI

• CAMK

  Ca²⁺/calmodulin-dependent protein kinase

• CPK

• CYP

• 1,25D

• 25D

• DAG

• DBP

  vitamin D-binding protein

• DEXA

  dual-energy x-ray absorptiometry

• EMG

• FFA

• FGF23

  fibroblast growth factor 23

• GLUT4

• HbA1c

• HOMA-IR

  homeostasis model assessment of insulin resistance

• IP3

• IRS

  insulin receptor substrate

• MHC

• MRI

  magnetic resonance imaging

• myf5

  myogenic transcription factor 5

• ODN

• 1α-OHD₃

• PKA

• PKC

• RCT

  randomized controlled trial

• RXR

• SNP

  single-nucleotide polymorphism

• SOCE

  store-operated calcium entry

• SR

• SRC

  steroid receptor coactivator complex

• STST

• TUAG

• VDCC

  voltage-dependent calcium-channel

• VDR

• VDRE

  vitamin D response element

• VDRKO

References

1

Moreno

LA

,

Valtueña

J

,

Pérez-López

F

,

González-Gross

M

2011

Health effects related to low vitamin D concentrations: beyond bone metabolism

.

Ann Nutr Metab

59

:

22

–

27

2

Christakos

S

,

DeLuca

HF

2011

Vitamin D: is there a role in extraskeletal health?

Endocrinology

152

:

2930

–

2936

3

Holick

MF

2007

Vitamin D deficiency

.

N Engl J Med

357

:

266

–

281

4

Thacher

TD

,

Clarke

BL

2011

Vitamin D insufficiency

.

Mayo Clin Proc

86

:

50

–

60

5

van Schoor

NM

,

Lips

P

2011

Worldwide vitamin D status

.

Best Pract Res Clin Endocrinol Metab

25

:

671

–

680

6

Mithal

A

,

Wahl

DA

,

Bonjour

JP

,

Burckhardt

P

,

Dawson-Hughes

B

,

Eisman

JA

,

El-Hajj Fuleihan

G

,

Josse

RG

,

Lips

P

,

Morales-Torres

J

2009

Global vitamin D status and determinants of hypovitaminosis D

.

Osteoporos Int

20

:

1807

–

1820

7

Forrest

KY

,

Stuhldreher

WL

2011

Prevalence and correlates of vitamin D deficiency in US adults

.

Nutr Res

31

:

48

–

54

8

Ginde

AA

,

Liu

MC

,

Camargo

CA

2009

Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004

.

Arch Intern Med

169

:

626

–

632

9

Dawson-Hughes

B

,

Mithal

A

,

Bonjour

JP

,

Boonen

S

,

Burckhardt

P

,

Fuleihan

GE

,

Josse

RG

,

Lips

P

,

Morales-Torres

J

,

Yoshimura

N

2010

IOF position statement: vitamin D recommendations for older adults

.

Osteoporos Int

21

:

1151

–

1154

10

Holick

MF

,

Binkley

NC

,

Bischoff-Ferrari

HA

,

Gordon

CM

,

Hanley

DA

,

Heaney

RP

,

Murad

MH

,

Weaver

CM

2011

Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline

.

J Clin Endocrinol Metab

96

:

1911

–

1930

11

Ross

AC

,

Manson

JE

,

Abrams

SA

,

Aloia

JF

,

Brannon

PM

,

Clinton

SK

,

Durazo-Arvizu

RA

,

Gallagher

JC

,

Gallo

RL

,

Jones

G

,

Kovacs

CS

,

Mayne

ST

,

Rosen

CJ

,

Shapses

SA

2011

The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know

.

J Clin Endocrinol Metab

96

:

53

–

58

12

Rosen

CJ

,

Adams

JS

,

Bikle

DD

,

Black

DM

,

Demay

MB

,

Manson

JE

,

Murad

MH

,

Kovacs

CS

2012

The nonskeletal effects of vitamin D: an Endocrine Society scientific statement

.

Endocr Rev

33

:

456

–

492

13

Bouillon

R

,

Carmeliet

G

,

Verlinden

L

,

van Etten

E

,

Verstuyf

A

,

Luderer

HF

,

Lieben

L

,

Mathieu

C

,

Demay

M

2008

Vitamin D and human health: lessons from vitamin D receptor null mice

.

Endocr Rev

29

:

726

–

776

14

Monderson

F

2007

The majesty of Egyptian gods and temples: a book of Egyptian poems

.

Bloomington, IN

:

AuthorHouse

15

Mayer

E

1932

The curative value of light: sunlight and sun lamp in health and disease

.

Whitefish, MT

:

Kessinger Publishing

16

Spellberg

AE

1952

Increase of athletic effectiveness by systematic ultraviolet irradiation. [In German]

.

Strahlentherapie

88

:

567

–

570

17

Gorkin

Z

,

GM

,

Teslenko

NE

1938

The effect of ultraviolet irradiation upon training for 100m sprint

.

Fiziol Zh USSR

25

:

695

–

701

(Russian)

18

Lehmann

G

,

ME

1944

Ultraviolet irradiation and altitude fitness

.

Luftfahrtmedizin

9

:

37

–

43

(German)

19

Boland

R

1986

Role of vitamin D in skeletal muscle function

.

Endocr Rev

7

:

434

–

448

20

Buitrago

C

,

Boland

R

2010

Caveolae and caveolin-1 are implicated in 1α,25(OH)2-vitamin D₃-dependent modulation of Src, MAPK cascades and VDR localization in skeletal muscle cells

.

J Steroid Biochem Mol Biol

121

:

169

–

175

21

Endo

I

,

Inoue

D

,

Mitsui

T

,

Umaki

Y

,

Akaike

M

,

Yoshizawa

T

,

Kato

S

,

Matsumoto

T

2003

Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors

.

Endocrinology

144

:

5138

–

5144

22

Buitrago

C

,

González Pardo

V

,

de Boland

AR

2002

Nongenomic action of 1α,25(OH)₂-vitamin D₃. Activation of muscle cell PLCγ through the tyrosine kinase c-Src and PtdIns 3-kinase

.

Eur J Biochem

269

:

2506

–

2515

23

Murad

MH

,

Elamin

KB

,

Abu Elnour

NO

,

Elamin

MB

,

Alkatib

AA

,

Fatourechi

MM

,

Almandoz

JP

,

Mullan

RJ

,

Lane

MA

,

Liu

H

,

Erwin

PJ

,

Hensrud

DD

,

Montori

VM

2011

The effect of vitamin D on falls: a systematic review and meta-analysis

.

J Clin Endocrinol Metab

96

:

2997

–

3006

24

Stockton

KA

,

Mengersen

K

,

Paratz

JD

,

Kandiah

D

,

Bennell

KL

2011

Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis

.

Osteoporos Int

22

:

859

–

871

25

Simpson

RU

,

Thomas

GA

,

Arnold

AJ

1985

Identification of 1,25-dihydroxyvitamin D₃ receptors and activities in muscle

.

J Biol Chem

260

:

8882

–

8891

26

Costa

EM

,

Blau

HM

,

Feldman

D

1986

1,25-dihydroxyvitamin D₃ receptors and hormonal responses in cloned human skeletal muscle cells

.

Endocrinology

119

:

2214

–

2220

27

Wang

Y

,

DeLuca

HF

2011

Is the vitamin D receptor found in muscle?

Endocrinology

152

:

354

–

363

28

Li

YC

,

Pirro

AE

,

Amling

M

,

Delling

G

,

Baron

R

,

Bronson

R

,

Demay

MB

1997

Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia

.

Proc Natl Acad Sci USA

94

:

9831

–

9835

29

Bischoff-Ferrari

HA

,

Dawson-Hughes

B

,

Staehelin

HB

,

Orav

JE

,

Stuck

AE

,

Theiler

R

,

Wong

JB

,

Egli

A

,

Kiel

DP

,

Henschkowski

J

2009

Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials

.

BMJ

339

:

b3692

30

Latham

NK

,

Anderson

CS

,

Reid

IR

2003

Effects of vitamin D supplementation on strength, physical performance, and falls in older persons: a systematic review

.

J Am Geriatr Soc

51

:

1219

–

1226

31

Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium

2011

Dietary reference intakes for calcium and vitamin D

.

Ross

AC

,

Taylor

CL

,

Yaktine

AL

,

Del Valle

HB

, eds.

Washington, DC

:

National Academies Press

32

Mellanby

E

,

CM

1919

Experimental investigation on rickets

.

Lancet

196

:

407

–

412

33

McCollum

EV

,

SN

,

Pitz

W

1916

The relation of unidentified dietary factors, the fat-soluble A and water-soluble B of the diet to the growth promoting properties of milk

.

J Biol Chem

27

:

33

–

38

34

McCollum

EV

,

Simmonds

N

,

Becker

JE

,

Shipley

PG

1922

Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin which promotes calcium deposition

.

J Biol Chem

53

:

293

–

312

35

Hess

AF

1922

The prevention and cure of rickets by sunlight

.

Am J Public Health (NY)

12

:

104

–

107

36

Huldschinsky

K

1919

Curing rickets by artificial UV radiation

.

Dtsch med Wschr

45

:

712

–

713

[In German]

37

Goldblatt

H

,

Soames

KN

1923

A study of rats on a normal diet irradiated daily by the mercury vapour quartz lamp or kept in darkness

.

Biochem J

17

:

294

–

297

38

Windaus

A

,

Linsert

O

,

Luttringhaus

A

,

Weidlinch

G

1932

Uber das krystallistierte vitamin D2

.

492

:

226

–

231

39

Holick

MF

,

Richtand

NM

,

McNeill

SC

,

Holick

SA

,

Frommer

JE

,

Henley

JW

,

Potts

JT

1979

Isolation and identification of previtamin D₃ from the skin of rats exposed to ultraviolet irradiation

.

Biochemistry

18

:

1003

–

1008

40

Esvelt

RP

,

Schnoes

HK

,

DeLuca

HF

1979

Isolation and characterization of 1α-hydroxy-23-carboxytetranorvitamin D: a major metabolite of 1,25-dihydroxyvitamin D₃

.

Biochemistry

18

:

3977

–

3983

41

Matsuoka

LY

,

Wortsman

J

,

Dannenberg

MJ

,

Hollis

BW

,

Lu

Z

,

Holick

MF

1992

Clothing prevents ultraviolet-B radiation-dependent photosynthesis of vitamin D₃

.

J Clin Endocrinol Metab

75

:

1099

–

1103

42

Webb

AR

,

Kline

L

,

Holick

MF

1988

Influence of season and latitude on the cutaneous synthesis of vitamin D₃: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D₃ synthesis in human skin

.

J Clin Endocrinol Metab

67

:

373

–

378

43

Matsuoka

LY

,

Ide

L

,

Wortsman

J

,

MacLaughlin

JA

,

Holick

MF

1987

Sunscreens suppress cutaneous vitamin D₃ synthesis

.

J Clin Endocrinol Metab

64

:

1165

–

1168

44

Ponchon

G

,

Kennan

AL

,

DeLuca

HF

1969

"Activation" of vitamin D by the liver

.

J Clin Invest

48

:

2032

–

2037

45

Andersson

S

,

Jörnvall

H

1986

Sex differences in cytochrome P-450-dependent 25-hydroxylation of C27-steroids and vitamin D₃ in rat liver microsomes

.

J Biol Chem

261

:

16932

–

16936

46

Wikvall

K

2001

Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form

.

Int J Mol Med

7

:

201

–

209

47

Cheng

JB

,

Motola

DL

,

Mangelsdorf

DJ

,

Russell

DW

2003

De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase

.

J Biol Chem

278

:

38084

–

38093

48

Shinkyo

R

,

Sakaki

T

,

Kamakura

M

,

Ohta

M

,

Inouye

K

2004

Metabolism of vitamin D by human microsomal CYP2R1

.

Biochem Biophys Res Commun

324

:

451

–

457

49

Cheng

JB

,

Levine

MA

,

Bell

NH

,

Mangelsdorf

DJ

,

Russell

DW

2004

Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase

.

Proc Natl Acad Sci USA

101

:

7711

–

7715

50

Omdahl

JL

,

Morris

HA

,

May

BK

2002

Hydroxylase enzymes of the vitamin D pathway: expression, function, and regulation

.

Annu Rev Nutr

22

:

139

–

166

51

Anderson

PH

,

May

BK

,

Morris

HA

2003

Vitamin D metabolism: new concepts and clinical implications

.

Clin Biochem Rev

24

:

13

–

26

52

Shinki

T

,

Shimada

H

,

Wakino

S

,

Anazawa

H

,

Hayashi

M

,

Saruta

T

,

DeLuca

HF

,

Suda

T

1997

Cloning and expression of rat 25-hydroxyvitamin D₃-1α-hydroxylase cDNA

.

Proc Natl Acad Sci USA

94

:

12920

–

12925

53

Kitanaka

S

,

Takeyama

K

,

Murayama

A

,

Sato

T

,

Okumura

K

,

Nogami

M

,

Hasegawa

Y

,

Niimi

H

,

Yanagisawa

J

,

Tanaka

T

,

Kato

S

1998

Inactivating mutations in the 25-hydroxyvitamin D₃ 1α-hydroxylase gene in patients with pseudovitamin D-deficiency rickets

.

N Engl J Med

338

:

653

–

661

54

Dardenne

O

,

Prud'homme

J

,

Arabian

A

,

Glorieux

FH

,

St-Arnaud

R

2001

Targeted inactivation of the 25-hydroxyvitamin D₃-1_α-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets

.

Endocrinology

142

:

3135

–

3141

55

Lucas

PA

,

Woodhead

JS

,

Brown

RC

1988

Vitamin D₃ metabolites in chronic renal failure and after renal transplantation

.

Nephrol Dial Transplant

3

:

70

–

76

56

Lucas

PA

,

Brown

RC

,

Woodhead

JS

,

Coles

GA

1986

1,25-Dihydroxycholecalciferol and parathyroid hormone in advanced chronic renal failure: effects of simultaneous protein and phosphorus restriction

.

Clin Nephrol

25

:

7

–

10

57

Demetriou

ET

,

Pietras

SM

,

Holick

MF

2010

Hypercalcemia and soft tissue calcification owing to sarcoidosis: the sunlight-cola connection

.

J Bone Miner Res

25

:

1695

–

1699

58

Nykjaer

A

,

Dragun

D

,

Walther

D

,

Vorum

H

,

Jacobsen

C

,

Herz

J

,

Melsen

F

,

Christensen

EI

,

Willnow

TE

1999

An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D₃

.

Cell

96

:

507

–

515

59

Kaseda

R

,

Hosojima

M

,

Sato

H

,

Saito

A

2011

Role of megalin and cubilin in the metabolism of vitamin D₃

.

Ther Apher Dial

15

(

Suppl 1

):

14

–

17

60

Brenza

HL

,

DeLuca

HF

2000

Regulation of 25-hydroxyvitamin D₃ 1α-hydroxylase gene expression by parathyroid hormone and 1,25-dihydroxyvitamin D₃

.

Arch Biochem Biophys

381

:

143

–

152

61

Robinson

CJ

,

Spanos

E

,

James

MF

,

Pike

JW

,

Haussler

MR

,

Makeen

AM

,

Hillyard

CJ

,

MacIntyre

I

1982

Role of prolactin in vitamin D metabolism and calcium absorption during lactation in the rat

.

J Endocrinol

94

:

443

–

453

62

Pike

JW

,

Spanos

E

,

Colston

KW

,

MacIntyre

I

,

Haussler

MR

1978

Influence of estrogen on renal vitamin D hydroxylases and serum 1α,25-(OH)₂D₃ in chicks

.

Am J Physiol

235

:

E338

–

E343

63

White

JH

2012

Regulation of intracrine production of 1,25-dihydroxyvitamin D and its role in innate immune defense against infection

.

Arch Biochem Biophys

523

:

58

–

63

64

Anderson

PH

,

O'Loughlin

PD

,

May

BK

,

Morris

HA

2003

Quantification of mRNA for the vitamin D metabolizing enzymes CYP27B1 and CYP24 and vitamin D receptor in kidney using real-time reverse transcriptase-polymerase chain reaction

.

J Mol Endocrinol

31

:

123

–

132

65

Schlingmann

KP

,

Kaufmann

M

,

Weber

S

,

Irwin

A

,

Goos

C

,

John

U

,

Misselwitz

J

,

Klaus

G

,

Kuwertz-Bröking

E

,

Fehrenbach

H

,

Wingen

AM

,

Güran

T

,

Hoenderop

JG

,

Bindels

RJ

,

Prosser

DE

,

Jones

G

,

Konrad

M

2011

Mutations in CYP24A1 and idiopathic infantile hypercalcemia

.

N Engl J Med

365

:

410

–

421

66

Brumbaugh

PF

,

Haussler

MR

1974

1α,25-Dihydroxycholecalciferol receptors in intestine. I. Association of 1α,25-dihydroxycholecalciferol with intestinal mucosa chromatin

.

J Biol Chem

249

:

1251

–

1257

67

McDonnell

DP

,

Mangelsdorf

DJ

,

Pike

JW

,

Haussler

MR

,

O'Malley

BW

1987

Molecular cloning of complementary DNA encoding the avian receptor for vitamin D

.

Science

235

:

1214

–

1217

68

Rochel

N

,

Wurtz

JM

,

Mitschler

A

,

Klaholz

B

,

Moras

D

2000

The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand

.

Mol Cell

5

:

173

–

179

69

Norman

AW

2006

Vitamin D receptor: new assignments for an already busy receptor

.

Endocrinology

147

:

5542

–

5548

70

Smith

CL

,

O'Malley

BW

2004

Coregulator function: a key to understanding tissue specificity of selective receptor modulators

.

Endocr Rev

25

:

45

–

71

71

Takeshita

A

,

Ozawa

Y

,

Chin

WW

2000

Nuclear receptor coactivators facilitate vitamin D receptor homodimer action on direct repeat hormone response elements

.

Endocrinology

141

:

1281

–

1284

72

Haussler

MR

,

Whitfield

GK

,

Haussler

CA

,

Hsieh

JC

,

Thompson

PD

,

Selznick

SH

,

Dominguez

CE

,

Jurutka

PW

1998

The nuclear vitamin D receptor: biological and molecular regulatory properties revealed

.

J Bone Miner Res

13

:

325

–

349

73

Umesono

K

,

Murakami

KK

,

Thompson

CC

,

Evans

RM

1991

Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D₃ receptors

.

Cell

65

:

1255

–

1266

74

Carlberg

C

,

Bendik

I

,

Wyss

A

,

Meier

E

,

Sturzenbecker

LJ

,

Grippo

JF

,

Hunziker

W

1993

Two nuclear signalling pathways for vitamin D

.

Nature

361

:

657

–

660

75

Dowd

DR

,

Sutton

AL

,

Zhang

C

,

MacDonald

P

2005

Comodulators of VDR-mediated gene expression

. In: ,

Feldman

D

,

Pike

JW

,

Glorieux

FH

, eds.

Vitamin D

. 2nd ed.

San Diego

:

Elsevier/Academic Press

;

291

–

304

76

Pike

JW

,

Meyer

MB

2010

The vitamin D receptor: new paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D₃

.

Endocrinol Metab Clin North Am

39

:

255

–

269

77

Ellison

TI

,

Eckert

RL

,

MacDonald

PN

2007

Evidence for 1,25-dihydroxyvitamin D₃-independent transactivation by the vitamin D receptor: uncoupling the receptor and ligand in keratinocytes

.

J Biol Chem

282

:

10953

–

10962

78

Prosser

DE

,

Jones

G

2004

Enzymes involved in the activation and inactivation of vitamin D

.

Trends Biochem Sci

29

:

664

–

673

79

Costa

EM

,

Hirst

MA

,

Feldman

D

1985

Regulation of 1,25-dihydroxyvitamin D₃ receptors by vitamin D analogs in cultured mammalian cells

.

Endocrinology

117

:

2203

–

2210

80

Christakos

S

,

Ajibade

DV

,

Dhawan

P

,

Fechner

AJ

,

Mady

LJ

2010

Vitamin D: metabolism

.

Endocrinol Metab Clin North Am

39

:

243

–

253

,

table of contents

81

Guyton

AC

,

Hall

JE

1996

Contraction of skeletal muscle

. In: ,

Guyton

AC

,

Hall

JE

, eds.

Textbook of medical physiology

.

Philadelphia

:

WB Saunders

;

73

–

93

82

Berchtold

MW

,

Brinkmeier

H

,

Müntener

M

2000

Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease

.

Physiol Rev

80

:

1215

–

1265

83

Brooke

MH

,

Kaiser

KK

1970

Muscle fiber types: how many and what kind?

Arch Neurol

23

:

369

–

379

84

Scott

W

,

Stevens

J

,

Binder-Macleod

SA

2001

Human skeletal muscle fiber type classifications

.

Phys Ther

81

:

1810

–

1816

85

Sato

Y

,

Iwamoto

J

,

Kanoko

T

,

Satoh

K

2005

Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial

.

Cerebrovasc Dis

20

:

187

–

192

86

Gordon

AM

,

Homsher

E

,

Regnier

M

2000

Regulation of contraction in striated muscle

.

Physiol Rev

80

:

853

–

924

87

Matthews

VB

,

Aström

MB

,

Chan

MH

,

Bruce

CR

,

Krabbe

KS

,

Prelovsek

O

,

Akerström

T

,

Yfanti

C

,

Broholm

C

,

Mortensen

OH

,

Penkowa

M

,

Hojman

P

,

Zankari

A

,

Watt

MJ

,

Bruunsgaard

H

,

Pedersen

BK

,

Febbraio

MA

2009

Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase

.

Diabetologia

52

:

1409

–

1418

88

Pedersen

BK

2009

Edward F. Adolph distinguished lecture: muscle as an endocrine organ: IL-6 and other myokines

.

J Appl Physiol

107

:

1006

–

1014

89

Pedersen

BK

,

Febbraio

MA

2008

Muscle as an endocrine organ: focus on muscle-derived interleukin-6

.

Physiol Rev

88

:

1379

–

1406

90

Dirks-Naylor

AJ

,

Lennon-Edwards

S

2011

The effects of vitamin D on skeletal muscle function and cellular signaling

.

J Steroid Biochem Mol Biol

125

:

159

–

168

91

Huxley

AF

,

Niedergerke

R

1954

Structural changes in muscle during contraction; interference microscopy of living muscle fibres

.

Nature

173

:

971

–

973

92

Ojuka

EO

,

Jones

TE

,

Nolte

LA

,

Chen

M

,

Wamhoff

BR

,

Sturek

M

,

Holloszy

JO

2002

Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca²⁺

.

Am J Physiol Endocrinol Metab

282

:

E1008

–

E1013

93

Ojuka

EO

2004

Role of calcium and AMP kinase in the regulation of mitochondrial biogenesis and GLUT4 levels in muscle

.

Proc Nutr Soc

63

:

275

–

278

94

Wright

DC

,

Hucker

KA

,

Holloszy

JO

,

Han

DH

2004

Ca²⁺ and AMPK both mediate stimulation of glucose transport by muscle contractions

.

Diabetes

53

:

330

–

335

95

Witczak

CA

,

Fujii

N

,

Hirshman

MF

,

Goodyear

LJ

2007

Ca²⁺/calmodulin-dependent protein kinase kinase-α regulates skeletal muscle glucose uptake independent of AMP-activated protein kinase and Akt activation

.

Diabetes

56

:

1403

–

1409

96

Lanner

JT

,

Katz

A

,

Tavi

P

,

Sandström

ME

,

Zhang

S-J

,

Wretman

C

,

James

S

,

Fauconnier

J

,

Lännergren

J

,

Bruton

JD

,

Westerblad

H

2006

The role of Ca²⁺ influx for insulin-mediated glucose uptake in skeletal muscle

.

Diabetes

55

:

2077

–

2083

97

Li

Y

,

Wang

P

,

Xu

J

,

Gorelick

F

,

Yamazaki

H

,

Andrews

N

,

Desir

GV

2007

Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII

.

Biochem Biophys Res Commun

362

:

658

–

664

98

Lanner

JT

,

Bruton

JD

,

Katz

A

,

Westerblad

H

2008

Ca²⁺ and insulin-mediated glucose uptake

.

Curr Opin Pharmacol

8

:

339

–

345

99

Gundersen

K

2011

Excitation-transcription coupling in skeletal muscle: the molecular pathways of exercise

.

Biol Rev Camb Philos Soc

86

:

564

–

600

100

Tavi

P

,

Westerblad

H

2011

The role of in vivo Ca²⁺ signals acting on Ca²⁺-calmodulin-dependent proteins for skeletal muscle plasticity

.

J Physiol

589

:

5021

–

5031

101

Michel

RN

,

Chin

ER

,

Chakkalakal

JV

,

Eibl

JK

,

Jasmin

BJ

2007

Ca²⁺/calmodulin-based signalling in the regulation of the muscle fibre phenotype and its therapeutic potential via modulation of utrophin A and myostatin expression

.

Appl Physiol Nutr Metab

32

:

921

–

929

102

Ryder

JW

,

Gilbert

M

,

Zierath

JR

2001

Skeletal muscle and insulin sensitivity: pathophysiological alterations

.

Front Biosci

6

:

D154

–

D163

103

Taniguchi

CM

,

Emanuelli

B

,

Kahn

CR

2006

Critical nodes in signalling pathways: insights into insulin action

.

Nat Rev Mol Cell Biol

7

:

85

–

96

104

Cheatham

B

,

Kahn

CR

1995

Insulin action and the insulin signaling network

.

Endocr Rev

16

:

117

–

142

105

Huang

S

,

Czech

MP

2007

The GLUT4 glucose transporter

.

Cell Metab

5

:

237

–

252

106

Munshi

HG

,

Burks

DJ

,

Joyal

JL

,

White

MF

,

Sacks

DB

1996

Ca²⁺ regulates calmodulin binding to IQ motifs in IRS-1

.

Biochemistry

35

:

15883

–

15889

107

Haussler

MR

,

Norman

AW

1969

Chromosomal receptor for a vitamin D metabolite

.

Proc Natl Acad Sci USA

62

:

155

–

162

108

Walters

MR

,

Hunziker

W

,

Norman

AW

1980

Cytosol preparations are inadequate for quantitating unoccupied receptors for 1,25-dihydroxyvitamin D₃

.

J Recept Res

1

:

313

–

327

109

Nemere

I

,

Schwartz

Z

,

Pedrozo

H

,

Sylvia

VL

,

Dean

DD

,

Boyan

BD

1998

Identification of a membrane receptor for 1,25-dihydroxyvitamin D₃ which mediates rapid activation of protein kinase C

.

J Bone Miner Res

13

:

1353

–

1359

110

Huhtakangas

JA

,

Olivera

CJ

,

Bishop

JE

,

Zanello

LP

,

Norman

AW

2004

The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1α,25(OH)₂-vitamin D₃ in vivo and in vitro

.

Mol Endocrinol

18

:

2660

–

2671

111

Bula

CM

,

Huhtakangas

J

,

Olivera

C

,

Bishop

JE

,

Norman

AW

,

Henry

HL

2005

Presence of a truncated form of the vitamin D receptor (VDR) in a strain of VDR-knockout mice

.

Endocrinology

146

:

5581

–

5586

112

Bauman

VK

,

Valinietse

MY

,

Babarykin

DA

1984

Vitamin D₃ and 1,25-dihydroxyvitamin D₃ stimulate the skeletal muscle-calcium mobilization in rachitic chicks

.

Arch Biochem Biophys

231

:

211

–

216

113

Santillán

G

,

Katz

S

,

Vazquez

G

,

Boland

RL

2004

TRPC3-like protein and vitamin D receptor mediate 1α,25(OH)₂D₃-induced SOC influx in muscle cells

.

Int J Biochem Cell Biol

36

:

1910

–

1918

114

Santillán

G

,

Baldi

C

,

Katz

S

,

Vazquez

G

,

Boland

R

2004

Evidence that TRPC3 is a molecular component of the 1α,25(OH)₂D₃-activated capacitative calcium entry (CCE) in muscle and osteoblast cells

.

J Steroid Biochem Mol Biol

89–90

:

291

–

295

115

Bischoff

HA

,

Borchers

M

,

Gudat

F

,

Duermueller

U

,

Theiler

R

,

Stähelin

HB

,

Dick

W

2001

In situ detection of 1,25-dihydroxyvitamin D₃ receptor in human skeletal muscle tissue

.

Histochem J

33

:

19

–

24

116

Wang

Y

,

Becklund

BR

,

DeLuca

HF

2010

Identification of a highly specific and versatile vitamin D receptor antibody

.

Arch Biochem Biophys

494

:

166

–

177

117

Capiati

D

,

Benassati

S

,

Boland

RL

2002

1,25(OH)₂-Vitamin D₃ induces translocation of the vitamin D receptor (VDR) to the plasma membrane in skeletal muscle cells

.

J Cell Biochem

86

:

128

–

135

118

Garcia

LA

,

King

KK

,

Ferrini

MG

,

Norris

KC

,

Artaza

JN

2011

1,25(OH)₂Vitamin D₃ stimulates myogenic differentiation by inhibiting cell proliferation and modulating the expression of promyogenic growth factors and myostatin in C2C12 skeletal muscle cells

.

Endocrinology

152

:

2976

–

2986

119

Buitrago

C

,

Vazquez

G

,

De Boland

AR

,

Boland

RL

2000

Activation of Src kinase in skeletal muscle cells by 1,25-(OH₂)-vitamin D₃ correlates with tyrosine phosphorylation of the vitamin D receptor (VDR) and VDR-Src interaction

.

J Cell Biochem

79

:

274

–

281

120

Buitrago

C

,

Boland

R

,

de Boland

AR

2001

The tyrosine kinase c-Src is required for 1,25(OH)₂-vitamin D₃ signalling to the nucleus in muscle cells

.

Biochim Biophys Acta

1541

:

179

–

187

121

Grucza

RA

,

Bradshaw

JM

,

Fütterer

K

,

Waksman

G

1999

SH2 domains: from structure to energetics, a dual approach to the study of structure-function relationships

.

Med Res Rev

19

:

273

–

293

122

Mizwicki

MT

,

Keidel

D

,

Bula

CM

,

Bishop

JE

,

Zanello

LP

,

Wurtz

JM

,

Moras

D

,

Norman

AW

2004

Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH)₂-vitamin D₃ signaling

.

Proc Natl Acad Sci USA

101

:

12876

–

12881

123

Menegaz

D

,

Mizwicki

MT

,

Barrientos-Duran

A

,

Chen

N

,

Henry

HL

,

Norman

AW

2011

Vitamin D receptor (VDR) regulation of voltage-gated chloride channels by ligands preferring a VDR-alternative pocket (VDR-AP)

.

Mol Endocrinol

25

:

1289

–

1300

124

Baran

DT

,

Quail

JM

,

Ray

R

,

Leszyk

J

,

Honeyman

T

2000

Annexin II is the membrane receptor that mediates the rapid actions of 1α,25-dihydroxyvitamin D₃

.

J Cell Biochem

78

:

34

–

46

125

Mizwicki

MT

,

Bishop

JE

,

Olivera

CJ

,

Huhtakangas

J

,

Norman

AW

2004

Evidence that annexin II is not a putative membrane receptor for 1α,25(OH)₂-vitamin D₃

.

J Cell Biochem

91

:

852

–

863

126

Khanal

R

,

Nemere

I

2007

Membrane receptors for vitamin D metabolites

.

Crit Rev Eukaryot Gene Expr

17

:

31

–

47

127

Vazquez

G

,

Boland

R

,

de Boland

AR

1995

Modulation by 1,25(OH)₂-vitamin D₃ of the adenylyl cyclase/cyclic AMP pathway in rat and chick myoblasts

.

Biochim Biophys Acta

1269

:

91

–

97

128

Capiati

DA

,

Vazquez

G

,

Boland

RL

2001

Protein kinase Cα modulates the Ca²⁺ influx phase of the Ca²⁺ response to 1α,25-dihydroxy-vitamin-D₃ in skeletal muscle cells

.

Horm Metab Res

33

:

201

–

206

129

Boland

RL

2011

VDR activation of intracellular signaling pathways in skeletal muscle

.

Mol Cell Endocrinol

347

:

11

–

16

130

Morelli

S

,

de Boland

AR

,

Boland

RL

1993

Generation of inositol phosphates, diacylglycerol and calcium fluxes in myoblasts treated with 1,25-dihydroxyvitamin D₃

.

Biochem J

289

(

Pt 3

):

675

–

679

131

Vazquez

G

,

de Boland

AR

,

Boland

RL

2000

Involvement of calmodulin in 1α,25-dihydroxyvitamin D₃ stimulation of store-operated Ca²⁺ influx in skeletal muscle cells

.

J Biol Chem

275

:

16134

–

16138

132

Capiati

DA

,

Vazquez

G

,

Tellez Iñón

MT

,

Boland

RL

2000

Role of protein kinase C in 1,25(OH)₂-vitamin D₃ modulation of intracellular calcium during development of skeletal muscle cells in culture

.

J Cell Biochem

77

:

200

–

212

133

Vazquez

G

,

de Boland

AR

1996

Involvement of protein kinase C in the modulation of 1α,25-dihydroxy-vitamin D₃-induced 45Ca²⁺ uptake in rat and chick cultured myoblasts

.

Biochim Biophys Acta

1310

:

157

–

162

134

Fernandez

LM

,

Massheimer

V

,

de Boland

AR

1990

Cyclic AMP-dependent membrane protein phosphorylation and calmodulin binding are involved in the rapid stimulation of muscle calcium uptake by 1,25-dihydroxyvitamin D₃

.

Calcif Tissue Int

47

:

314

–

319

135

Vazquez

G

,

de Boland

AR

,

Boland

RL

1997

1a,25-(OH)2-Vitamin D3 stimulates the adenylyl cyclase pathway in muscle cells by a GTP-dependent mechanism which presumably involves phosphorylation of Gai

.

Biochem Biophys Res Commun

234

:

125

–

128

136

Curry

OB

,

Basten

JF

,

Francis

MJ

,

Smith

R

1974

Calcium uptake by sarcoplasmic reticulum of muscle from vitamin D-deficient rabbits

.

Nature

249

:

83

–

84

137

Birge

SJ

,

Haddad

JG

1975

25-hydroxycholecalciferol stimulation of muscle metabolism

.

J Clin Invest

56

:

1100

–

1107

138

Bellido

T

,

Boland

RL

1985

In vitro muscle phosphate uptake. Characteristics and action of vitamin D₃ metabolites

. In: ,

Norman

AW

,

Schaefer

H

,

Grigoleit

HG

, eds.

Vitamin D: a chemical, biochemical, and clinical update

.

Berlin

:

Walter de Gruyter

; pp.

590

–

591

139

De Boland

AR

,

Gallego

S

,

Boland

R

1983

Effects of vitamin D-3 on phosphate and calcium transport across and composition of skeletal muscle plasma cell membranes

.

Biochim Biophys Acta

733

:

264

–

273

140

Boland

R

,

Matthews

C

,

de Boland

AR

,

Ritz

E

,

Hasselbach

W

1983

Reversal of decreased phosphorylation of sarcoplasmic reticulum calcium transport ATPase by 1,25-dihydroxycholecalciferol in experimental uremia

.

Calcif Tissue Int

35

:

195

–

201

141

de Boland

AR

,

Albornoz

LE

,

Boland

R

1983

The effect of cholecalciferol in vivo on proteins and lipids of skeletal muscle from rachitic chicks

.

Calcif Tissue Int

35

:

798

–

805

142

Morelli

S

,

Buitrago

C

,

Boland

R

,

de Boland

AR

2001

The stimulation of MAP kinase by 1,25(OH)₂-vitamin D₃ in skeletal muscle cells is mediated by protein kinase C and calcium

.

Mol Cell Endocrinol

173

:

41

–

52

143

Buitrago

CG

,

Pardo

VG

,

de Boland

AR

,

Boland

R

2003

Activation of RAF-1 through Ras and protein kinase Cα mediates 1α,25(OH)₂-vitamin D₃ regulation of the mitogen-activated protein kinase pathway in muscle cells

.

J Biol Chem

278

:

2199

–

2205

144

Ronda

AC

,

Buitrago

C

,

Colicheo

A

,

de Boland

AR

,

Roldán

E

,

Boland

R

2007

Activation of MAPKs by 1α,25(OH)₂-vitamin D₃ and 17β-estradiol in skeletal muscle cells leads to phosphorylation of Elk-1 and CREB transcription factors

.

J Steroid Biochem Mol Biol

103

:

462

–

466

145

Boland

R

,

De Boland

AR

,

Buitrago

C

,

Morelli

S

,

Santillán

G

,

Vazquez

G

,

Capiati

D

,

Baldi

C

2002

Non-genomic stimulation of tyrosine phosphorylation cascades by 1,25(OH)₂D₃ by VDR-dependent and -independent mechanisms in muscle cells

.

Steroids

67

:

477

–

482

146

Buitrago

CG

,

Ronda

AC

,

de Boland

AR

,

Boland

R

2006

MAP kinases p38 and JNK are activated by the steroid hormone 1α,25(OH)₂-vitamin D₃ in the C2C12 muscle cell line

.

J Cell Biochem

97

:

698

–

708

147

An

SS

,

Fabry

B

,

Mellema

M

,

Bursac

P

,

Gerthoffer

WT

,

Kayyali

US

,

Gaestel

M

,

Shore

SA

,

Fredberg

JJ

2004

Role of heat shock protein 27 in cytoskeletal remodeling of the airway smooth muscle cell

.

J Appl Physiol

96

:

1701

–

1713

148

Buitrago

CG

,

Arango

NS

,

Boland

RL

2012

1α,25(OH)₂ D₃ -dependent modulation of Akt in proliferating and differentiating C2C12 skeletal muscle cells

.

J Cell Biochem

113

:

1170

–

1181

149

Alami-Durante

H

,

Cluzeaud

M

,

Bazin

D

,

Mazurais

D

,

Zambonino-Infante

JL

2011

Dietary cholecalciferol regulates the recruitment and growth of skeletal muscle fibers and the expressions of myogenic regulatory factors and the myosin heavy chain in European sea bass larvae

.

J Nutr

141

:

2146

–

2151

150

Braun

T

,

Gautel

M

2011

Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis

.

Nat Rev Mol Cell Biol

12

:

349

–

361

151

Pointon

JJ

,

Francis

MJ

,

Smith

R

1979

Effect of vitamin D deficiency on sarcoplasmic reticulum function and troponin C concentration of rabbit skeletal muscle

.

Clin Sci (Lond)

57

:

257

–

263

152

Ströder

J

,

Arensmeyer

E

1965

[Actomyosin content of the skeletal muscles in experimental rickets]

.

Klin Wochenschr

43

:

1201

–

1202

(German)

153

Min

Y

,

Lowy

C

,

Islam

S

,

Khan

FS

,

Swaminathan

R

2011

Relationship between red cell membrane fatty acids and adipokines in individuals with varying insulin sensitivity

.

Eur J Clin Nutr

65

:

690

–

695

154

de Boland

AR

,

Boland

R

1985

Suppression of 1,25-dihydroxy-vitamin D₃-dependent calcium transport by protein synthesis inhibitors and changes in phospholipids in skeletal muscle

.

Biochim Biophys Acta

845

:

237

–

241

155

Breen

ME

,

Laing

EM

,

Hall

DB

,

Hausman

DB

,

Taylor

RG

,

Isales

CM

,

Ding

KH

,

Pollock

NK

,

Hamrick

MW

,

Baile

CA

,

Lewis

RD

2011

25-Hydroxyvitamin D, insulin-like growth factor-I, and bone mineral accrual during growth

.

J Clin Endocrinol Metab

96

:

E89

–

E98

156

Willis

CM

,

Laing

EM

,

Hall

DB

,

Hausman

DB

,

Lewis

RD

2007

A prospective analysis of plasma 25-hydroxyvitamin D concentrations in white and black prepubertal females in the southeastern United States

.

Am J Clin Nutr

85

:

124

–

130

157

Rauch

F

,

Bailey

DA

,

Baxter-Jones

A

,

Mirwald

R

,

Faulkner

R

2004

The 'muscle-bone unit' during the pubertal growth spurt

.

Bone

34

:

771

–

775

158

Prié

D

,

Friedlander

G

2010

Reciprocal control of 1,25-dihydroxyvitamin D and FGF23 formation involving the FGF23/Klotho system

.

Clin J Am Soc Nephrol

5

:

1717

–

1722

159

Aono

Y

,

Hasegawa

H

,

Yamazaki

Y

,

Shimada

T

,

Fujita

T

,

Yamashita

T

,

Fukumoto

S

2011

Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice

.

J Bone Miner Res

26

:

803

–

810

160

Leal

MA

,

Aller

P

,

Mas

A

,

Calle

C

1995

The effect of 1,25-dihydroxyvitamin D₃ on insulin binding, insulin receptor mRNA levels, and isotype RNA pattern in U-937 human promonocytic cells

.

Exp Cell Res

217

:

189

–

194

161

Maestro

B

,

Campión

J

,

Dávila

N

,

Calle

C

2000

Stimulation by 1,25-dihydroxyvitamin D₃ of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells

.

Endocr J

47

:

383

–

391

162

Maestro

B

,

Dávila

N

,

Carranza

MC

,

Calle

C

2003

Identification of a Vitamin D response element in the human insulin receptor gene promoter

.

J Steroid Biochem Mol Biol

84

:

223

–

230

163

Zhou

QG

,

Hou

FF

,

Guo

ZJ

,

Liang

M

,

Wang

GB

,

Zhang

X

2008

1,25-Dihydroxyvitamin D improved the free fatty-acid-induced insulin resistance in cultured C2C12 cells

.

Diabetes Metab Res Rev

24

:

459

–

464

164

de Boland

AR

,

Boland

RL

1993

1,25-Dihydroxyvitamin D-3 induces arachidonate mobilization in embryonic chick myoblasts

.

Biochim Biophys Acta

1179

:

98

–

104

165

Boucher

BJ

2009

Does vitamin D status contribute to caveolin-1-mediated insulin sensitivity in skeletal muscle?

Diabetologia

52

:

2240

;

author reply 2241–2243

166

Oh

YS

,

Khil

LY

,

Cho

KA

,

Ryu

SJ

,

Ha

MK

,

Cheon

GJ

,

Lee

TS

,

Yoon

JW

,

Jun

HS

,

Park

SC

2008

A potential role for skeletal muscle caveolin-1 as an insulin sensitivity modulator in ageing-dependent non-obese type 2 diabetes: studies in a new mouse model

.

Diabetologia

51

:

1025

–

1034

167

Kim

CA

,

Delépine

M

,

Boutet

E

,

El Mourabit

H

,

Le Lay

S

,

Meier

M

,

Nemani

M

,

Bridel

E

,

Leite

CC

,

Bertola

DR

,

Semple

RK

,

O'Rahilly

S

,

Dugail

I

,

Capeau

J

,

Lathrop

M

,

Magré

J

2008

Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy

.

J Clin Endocrinol Metab

93

:

1129

–

1134

168

Kanakamani

J

,

Tomar

N

,

Kaushal

E

,

Tandon

N

,

Goswami

R

2010

Presence of a deletion mutation (c. 716delA) in the ligand binding domain of the vitamin D receptor in an Indian patient with vitamin D-dependent rickets type II

.

Calcif Tissue Int

86

:

33

–

41

169

Bergman

R

,

Schein-Goldshmid

R

,

Hochberg

Z

,

Ben-Izhak

O

,

Sprecher

E

2005

The alopecias associated with vitamin D-dependent rickets type IIA and with hairless gene mutations: a comparative clinical, histologic, and immunohistochemical study

.

Arch Dermatol

141

:

343

–

351

170

Seoane

S

,

Alonso

M

,

Segura

C

,

Pérez-Fernández

R

2002

Localization of a negative vitamin D response sequence in the human growth hormone gene

.

Biochem Biophys Res Commun

292

:

250

–

255

171

Sakoda

K

,

Fujiwara

M

,

Arai

S

,

Suzuki

A

,

Nishikawa

J

,

Imagawa

M

,

Nishihara

T

1996

Isolation of a genomic DNA fragment having negative vitamin D response element

.

Biochem Biophys Res Commun

219

:

31

–

35

172

Kalueff

AV

,

Lou

YR

,

Laaksi

I

,

Tuohimaa

P

2004

Increased anxiety in mice lacking vitamin D receptor gene

.

Neuroreport

15

:

1271

–

1274

173

Kalueff

AV

,

Lou

YR

,

Laaksi

I

,

Tuohimaa

P

2004

Impaired motor performance in mice lacking neurosteroid vitamin D receptors

.

Brain Res Bull

64

:

25

–

29

174

Burne

TH

,

Johnston

AN

,

McGrath

JJ

,

Mackay-Sim

A

2006

Swimming behaviour and post-swimming activity in Vitamin D receptor knockout mice

.

Brain Res Bull

69

:

74

–

78

175

Minasyan

A

,

Keisala

T

,

Zou

J

,

Zhang

Y

,

Toppila

E

,

Syvälä

H

,

Lou

YR

,

Kalueff

AV

,

Pyykkö

I

,

Tuohimaa

P

2009

Vestibular dysfunction in vitamin D receptor mutant mice

.

J Steroid Biochem Mol Biol

114

:

161

–

166

176

Schubert

L

,

DeLuca

HF

2010

Hypophosphatemia is responsible for skeletal muscle weakness of vitamin D deficiency

.

Arch Biochem Biophys

500

:

157

–

161

177

Rodman

JS

,

Baker

T

1978

Changes in the kinetics of muscle contraction in vitamin D-depleted rats

.

Kidney Int

13

:

189

–

193

178

Pleasure

D

,

Wyszynski

B

,

Sumner

A

,

Schotland

D

,

Feldman

B

,

Nugent

N

,

Hitz

K

,

Goodman

DB

1979

Skeletal muscle calcium metabolism and contractile force in vitamin D-deficient chicks

.

J Clin Invest

64

:

1157

–

1167

179

Tague

SE

,

Clarke

GL

,

Winter

MK

,

McCarson

KE

,

Wright

DE

,

Smith

PG

2011

Vitamin D deficiency promotes skeletal muscle hypersensitivity and sensory hyperinnervation

.

J Neurosci

31

:

13728

–

13738

180

Giulietti

A

,

Gysemans

C

,

Stoffels

K

,

van Etten

E

,

Decallonne

B

,

Overbergh

L

,

Bouillon

R

,

Mathieu

C

2004

Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice

.

Diabetologia

47

:

451

–

462

181

Kawashima

H

,

Castro

A

1981

Effect of 1α-hydroxyvitamin D₃ on the glucose and calcium metabolism in genetic obese mice

.

Res Commun Chem Pathol Pharmacol

33

:

155

–

161

182

Chang-Quan

H

,

Bi-Rong

D

,

Zhen-Chan

HPL

2008

Insufficient renal 1-alpha hydroxylase and bone homeostasis in aged rats with insulin resistance or type 2 diabetes mellitus

.

J Bone Miner Metab

26

:

561

–

568

183

Chen

S

,

Law

CS

,

Grigsby

CL

,

Olsen

K

,

Hong

TT

,

Zhang

Y

,

Yeghiazarians

Y

,

Gardner

DG

2011

Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy

.

Circulation

124

:

1838

–

1847

184

Whitfield

GK

,

Remus

LS

,

Jurutka

PW

,

Zitzer

H

,

Oza

AK

,

Dang

HT

,

Haussler

CA

,

Galligan

MA

,

Thatcher

ML

,

Encinas Dominguez

C

,

Haussler

MR

2001

Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene

.

Mol Cell Endocrinol

177

:

145

–

159

185

Roth

SM

,

Zmuda

JM

,

Cauley

JA

,

Shea

PR

,

Ferrell

RE

2004

Vitamin D receptor genotype is associated with fat-free mass and sarcopenia in elderly men

.

J Gerontol A Biol Sci Med Sci

59

:

10

–

15

186

Hopkinson

NS

,

Li

KW

,

Kehoe

A

,

Humphries

SE

,

Roughton

M

,

Moxham

J

,

Montgomery

H

,

Polkey

MI

2008

Vitamin D receptor genotypes influence quadriceps strength in chronic obstructive pulmonary disease

.

Am J Clin Nutr

87

:

385

–

390

187

Windelinckx

A

,

De Mars

G

,

Beunen

G

,

Aerssens

J

,

Delecluse

C

,

Lefevre

J

,

Thomis

MA

2007

Polymorphisms in the vitamin D receptor gene are associated with muscle strength in men and women

.

Osteoporos Int

18

:

1235

–

1242

188

Ceglia

L

2008

Vitamin D and skeletal muscle tissue and function

.

Mol Aspects Med

29

:

407

–

414

189

Geusens

P

,

Vandevyver

C

,

Vanhoof

J

,

Cassiman

JJ

,

Boonen

S

,

Raus

J

1997

Quadriceps and grip strength are related to vitamin D receptor genotype in elderly nonobese women

.

J Bone Miner Res

12

:

2082

–

2088

190

Grundberg

E

,

Brändström

H

,

Ribom

EL

,

Ljunggren

O

,

Mallmin

H

,

Kindmark

A

2004

Genetic variation in the human vitamin D receptor is associated with muscle strength, fat mass and body weight in Swedish women

.

Eur J Endocrinol

150

:

323

–

328

191

Wang

P

,

Ma

LH

,

Wang

HY

,

Zhang

W

,

Tian

Q

,

Cao

DN

,

Zheng

GX

,

Sun

YL

2006

Association between polymorphisms of vitamin D receptor gene ApaI, BsmI and TaqI and muscular strength in young Chinese women

.

Int J Sports Med

27

:

182

–

186

192

Bahat

G

,

Saka

B

,

Erten

N

,

Ozbek

U

,

Coskunpinar

E

,

Yildiz

S

,

Sahinkaya

T

,

Karan

MA

2010

BsmI polymorphism in the vitamin D receptor gene is associated with leg extensor muscle strength in elderly men

.

Aging Clin Exp Res

22

:

198

–

205

193

Onder

G

,

Capoluongo

E

,

Danese

P

,

Settanni

S

,

Russo

A

,

Concolino

P

,

Bernabei

R

,

Landi

F

2008

Vitamin D receptor polymorphisms and falls among older adults living in the community: results from the ilSIRENTE study

.

J Bone Miner Res

23

:

1031

–

1036

194

Barr

R

,

Macdonald

H

,

Stewart

A

,

McGuigan

F

,

Rogers

A

,

Eastell

R

,

Felsenberg

D

,

Glüer

C

,

Roux

C

,

Reid

DM

2010

Association between vitamin D receptor gene polymorphisms, falls, balance and muscle power: results from two independent studies (APOSS and OPUS)

.

Osteoporos Int

21

:

457

–

466

195

Clifton-Bligh

RJ

,

Nguyen

TV

,

Au

A

,

Bullock

M

,

Cameron

I

,

Cumming

R

,

Chen

JS

,

March

LM

,

Seibel

MJ

,

Sambrook

PN

2011

Contribution of a common variant in the promoter of the 1-α-hydroxylase gene (CYP27B1) to fracture risk in the elderly

.

Calcif Tissue Int

88

:

109

–

116

196

Whistler

D

1645

De morbo puerili Anglorum quem patrio idiomate indigenae vocant the rickets. University of Leidon doctoral dissertation

.

Oxford

:

Alexander Cooke

197

Glisson

F

1651

A treatise of the rickets: being a disease common to children

. ,

Culpeper

N

, ed.

London

:

P Cole

198

Chalmers

J

,

Conacher

WD

,

Gardner

DL

,

Scott

PJ

1967

Osteomalacia: a common disease in elderly women

.

J Bone Joint Surg Br

49

:

403

–

423

199

Chalmers

J

,

Conacher

W

,

Gardner

D

,

Scott

P

1967

Osteomalacia: a common disease in elderly women

.

J Bone Joint Surg Br

49

:

403

–

423

200

Russell

JA

1994

Osteomalacic myopathy

.

Muscle Nerve

17

:

578

–

580

201

Irani

PF

1976

Electromyography in nutritional osteomalacic myopathy

.

J Neurol Neurosurg Psychiatry

39

:

686

–

693

202

Schott

GD

,

Wills

MR

1976

Muscle weakness in osteomalacia

.

Lancet

1

:

626

–

629

203

Floyd

M

,

Ayyar

DR

,

Barwick

DD

,

Hudgson

P

,

Weightman

D

1974

Myopathy in chronic renal failure

.

Q J Med

43

:

509

–

524

204

Amstrup

AK

,

Rejnmark

L

,

Vestergaard

P

,

Sikjaer

T

,

Rolighed

L

,

Heickendorff

L

,

Mosekilde

L

2011

Vitamin D status, physical performance and body mass in patients surgically cured for primary hyperparathyroidism compared with healthy controls: a cross-sectional study

.

Clin Endocrinol (Oxf)

74

:

130

–

136

205

Al-Said

YA

,

Al-Rached

HS

,

Al-Qahtani

HA

,

Jan

MM

2009

Severe proximal myopathy with remarkable recovery after vitamin D treatment

.

Can J Neurol Sci

36

:

336

–

339

206

Hamilton

B

2010

Vitamin D and human skeletal muscle

.

Scand J Med Sci Sports

20

:

182

–

190

207

Ziambaras

K

,

Dagogo-Jack

S

1997

Reversible muscle weakness in patients with vitamin D deficiency

.

West J Med

167

:

435

–

439

208

Glerup

H

,

Mikkelsen

K

,

Poulsen

L

,

Hass

E

,

Overbeck

S

,

Andersen

H

,

Charles

P

,

Eriksen

EF

2000

Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement

.

Calcif Tissue Int

66

:

419

–

424

209

Prabhala

A

,

Garg

R

,

Dandona

P

2000

Severe myopathy associated with vitamin D deficiency in western New York

.

Arch Intern Med

160

:

1199

–

1203

210

Whitaker

CH

,

Malchoff

CD

,

Felice

KJ

2000

Treatable lower motor neuron disease due to vitamin D deficiency and secondary hyperparathyroidism

.

Amyotroph Lateral Scler Other Motor Neuron Disord

1

:

283

–

286

211

Plotnikoff

GA

,

Quigley

JM

2003

Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain

.

Mayo Clin Proc

78

:

1463

–

1470

212

Macfarlane

G

,

Palmer

B

,

Roy

D

,

Afzal

C

,

Silman

A

,

O'Neill

T

2005

An excess of widespread pain among South Asians: are low levels of vitamin D implicated?

Ann Rheum Dis

64

:

1217

–

1219

213

Mouyis

M

,

Ostor

AJ

,

Crisp

AJ

,

Ginawi

A

,

Halsall

DJ

,

Shenker

N

,

Poole

KE

2008

Hypovitaminosis D among rheumatology outpatients in clinical practice

.

Rheumatology (Oxford)

47

:

1348

–

1351

214

Warner

AE

,

Arnspiger

SA

2008

Diffuse musculoskeletal pain is not associated with low vitamin D levels or improved by treatment with vitamin D

.

J Clin Rheumatol

14

:

12

–

16

215

Block

SR

2004

Vitamin D deficiency is not associated with nonspecific musculoskeletal pain syndromes including fibromyalgia

.

Mayo Clin Proc

79

:

1585

–

1586

;

author reply 1586–1587

216

Myers

KJ

2004

Vitamin D deficiency and chronic pain: cause and effect or epiphenomenon?

Mayo Clin Proc

79

:

695

;

author reply 695–696

217

McBeth

J

,

Pye

SR

,

O'Neill

TW

,

Macfarlane

GJ

,

Tajar

A

,

Bartfai

G

,

Boonen

S

,

Bouillon

R

,

Casanueva

F

,

Finn

JD

,

Forti

G

,

Giwercman

A

,

Han

TS

,

Huhtaniemi

IT

,

Kula

K

,

Lean

ME

,

Pendleton

N

,

Punab

M

,

Silman

AJ

,

Vanderschueren

D

,

Wu

FC

2010

Musculoskeletal pain is associated with very low levels of vitamin D in men: results from the European Male Ageing Study

.

Ann Rheum Dis

69

:

1448

–

1452

218

Ford

JA

,

Colhoun

EM

,

McIntosh

WB

,

Dunnigan

MG

1972

Rickets and osteomalacia in the Glasgow Pakistani community, 1961–71

.

Br Med J

2

:

677

–

680

219

Preece

MA

,

McIntosh

WB

,

Tomlinson

S

,

Ford

JA

,

Dunnigan

MG

,

O'Riordan

JL

1973

Vitamin-D deficiency among Asian immigrants to Britain

.

Lancet

1

:

907

–

910

220

de Torrenté de la Jara

G

,

Pécoud

A

,

Favrat

B

2006

Female asylum seekers with musculoskeletal pain: the importance of diagnosis and treatment of hypovitaminosis D

.

BMC Fam Pract

7

:

4

221

Badsha

H

,

Daher

M

,

Ooi Kong

K

2009

Myalgias or non-specific muscle pain in Arab or Indo-Pakistani patients may indicate vitamin D deficiency

.

Clin Rheumatol

28

:

971

–

973

222

Nellen

JF

,

Smulders

YM

,

Jos Frissen

PH

,

Slaats

EH

,

Silberbusch

J

1996

Hypovitaminosis D in immigrant women: slow to be diagnosed

.

BMJ

312

:

570

–

572

223

Benson

J

,

Wilson

A

,

Stocks

N

,

Moulding

N

2006

Muscle pain as an indicator of vitamin D deficiency in an urban Australian Aboriginal population

.

Med J Aust

185

:

76

–

77

224

Dupont

WD

,

Plummer

WD

1997

PS power and sample size program available for free on the Internet

.

Control Clin Trials

18

:

274

225

Reginato

AJ

,

Coquia

JA

2003

Musculoskeletal manifestations of osteomalacia and rickets

.

Best Pract Res Clin Rheumatol

17

:

1063

–

1080

226

Gloth

FM

,

Lindsay

JM

,

Zelesnick

LB

,

Greenough

WB

1991

Can vitamin D deficiency produce an unusual pain syndrome?

Arch Intern Med

151

:

1662

–

1664

227

Atherton

K

,

Berry

DJ

,

Parsons

T

,

Macfarlane

GJ

,

Power

C

,

Hyppönen

E

2009

Vitamin D and chronic widespread pain in a white middle-aged British population: evidence from a cross-sectional population survey

.

Ann Rheum Dis

68

:

817

–

822

228

de Rezende Pena

C

,

Grillo

LP

,

das Chagas Medeiros

MM

2010

Evaluation of 25-hydroxyvitamin D serum levels in patients with fibromyalgia

.

J Clin Rheumatol

16

:

365

–

369

229

Al-Allaf

AW

,

Mole

PA

,

Paterson

CR

,

Pullar

T

2003

Bone health in patients with fibromyalgia

.

Rheumatology (Oxford)

42

:

1202

–

1206

230

Arvold

DS

,

Odean

MJ

,

Dornfeld

MP

,

Regal

RR

,

Arvold

JG

,

Karwoski

GC

,

Mast

DJ

,

Sanford

PB

,

Sjoberg

RJ

2009

Correlation of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment: a randomized controlled trial

.

Endocr Pract

15

:

203

–

212

231

Khan

QJ

,

Reddy

PS

,

Kimler

BF

,

Sharma

P

,

Baxa

SE

,

O'Dea

AP

,

Klemp

JR

,

Fabian

CJ

2010

Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer

.

Breast Cancer Res Treat

119

:

111

–

118

232

Rastelli

AL

,

Taylor

ME

,

Gao

F

,

Armamento-Villareal

R

,

JAMAlabadi-Majidi

S

,

Napoli

N

,

Ellis

MJ

2011

Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial

.

Breast Cancer Res Treat

129

:

107

–

116

233

Gupta

A

,

Thompson

PD

2011

The relationship of vitamin D deficiency to statin myopathy

.

Atherosclerosis

215

:

23

–

29

234

Lee

JH

,

O'Keefe

JH

,

Bell

D

,

Hensrud

DD

,

Holick

MF

2008

Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor?

J Am Coll Cardiol

52

:

1949

–

1956

235

Goldstein

MR

2007

Myopathy, statins, and vitamin D deficiency

.

Am J Cardiol

100

:

1328

236

Bell

DS

2010

Resolution of statin-induced myalgias by correcting vitamin D deficiency

.

South Med J

103

:

690

–

692

237

Backes

JM

,

Barnes

BJ

,

Ruisinger

JF

,

Moriarty

PM

2011

A comparison of 25-hydroxyvitamin D serum levels among those with or without statin-associated myalgias

.

Atherosclerosis

218

:

247

–

249

238

Ahmed

W

,

Khan

N

,

Glueck

CJ

,

Pandey

S

,

Wang

P

,

Goldenberg

N

,

Uppal

M

,

Khanal

S

2009

Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients

.

Transl Res

153

:

11

–

16

239

Lee

P

,

Greenfield

JR

,

Campbell

LV

2009

Vitamin D insufficiency: a novel mechanism of statin-induced myalgia?

Clin Endocrinol (Oxf)

71

:

154

–

155

240

Glueck

CJ

,

Budhani

SB

,

Masineni

SS

,

Abuchaibe

C

,

Khan

N

,

Wang

P

,

Goldenberg

N

2011

Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance

.

Curr Med Res Opin

27

:

1683

–

1690

241

Linde

R

,

Peng

L

,

Desai

M

,

Feldman

D

2010

The role of vitamin D and SLCO1B1*5 gene polymorphism in statin-associated myalgias

.

Dermatoendocrinol

2

:

77

–

84

242

Kurnik

D

,

Hochman

I

,

Vesterman-Landes

J

,

Kenig

T

,

Katzir

I

,

Lomnicky

Y

,

Halkin

H

,

Loebstein

R

2011

Muscle pain and serum creatine kinase are not associated with low serum 25(OH) vitamin D levels in patients receiving statins

.

Clin Endocrinol (Oxf)

77

:

36

–

41

243

Rejnmark

L

,

Vestergaard

P

,

Heickendorff

L

,

Mosekilde

L

2010

Simvastatin does not affect vitamin D status, but low vitamin D levels are associated with dyslipidemia: results from a randomised, controlled trial

.

Int J Endocrinol

2010

:

957174

244

Dobs

AS

,

Levine

MA

,

Margolis

S

1991

Effects of pravastatin, a new HMG-CoA reductase inhibitor, on vitamin D synthesis in man

.

Metabolism

40

:

524

–

528

245

Gupta

RP

,

Hollis

BW

,

Patel

SB

,

Patrick

KS

,

Bell

NH

2004

CYP3A4 is a human microsomal vitamin D 25-hydroxylase

.

J Bone Miner Res

19

:

680

–

688

246

Gillespie

LD

,

Gillespie

WJ

,

Robertson

MC

,

Lamb

SE

,

Cumming

RG

,

Rowe

BH

2003

Interventions for preventing falls in elderly people

.

Cochrane Database Syst Rev

2003

:

CD000340

247

Vellas

BJ

,

Wayne

SJ

,

Romero

LJ

,

Baumgartner

RN

,

Garry

PJ

1997

Fear of falling and restriction of mobility in elderly fallers

.

Age Ageing

26

:

189

–

193

248

Marzetti

E

,

Leeuwenburgh

C

2006

Skeletal muscle apoptosis, sarcopenia and frailty at old age

.

Exp Gerontol

41

:

1234

–

1238

249

Campbell

AJ

,

Spears

GF

,

Borrie

MJ

,

Fitzgerald

JL

1988

Falls, elderly women and the cold

.

Gerontology

34

:

205

–

208

250

Flicker

L

,

Mead

K

,

MacInnis

RJ

,

Nowson

C

,

Scherer

S

,

Stein

MS

,

Thomasx

J

,

Hopper

JL

,

Wark

JD

2003

Serum vitamin D and falls in older women in residential care in Australia

.

J Am Geriatr Soc

51

:

1533

–

1538

251

Snijder

MB

,

van Schoor

NM

,

Pluijm

SM

,

van Dam

RM

,

Visser

M

,

Lips

P

2006

Vitamin D status in relation to one-year risk of recurrent falling in older men and women

.

J Clin Endocrinol Metab

91

:

2980

–

2985

252

Stein

MS

,

Wark

JD

,

Scherer

SC

,

Walton

SL

,

Chick

P

,

Di Carlantonio

M

,

Zajac

JD

,

Flicker

L

1999

Falls relate to vitamin D and parathyroid hormone in an Australian nursing home and hostel

.

J Am Geriatr Soc

47

:

1195

–

1201

253

Sambrook

PN

,

Cameron

ID

,

Chen

JS

,

Cumming

RG

,

Durvasula

S

,

Herrmann

M

,

Kok

C

,

Lord

SR

,

Macara

M

,

March

LM

,

Mason

RS

,

Seibel

MJ

,

Wilson

N

,

Simpson

JM

2012

Does increased sunlight exposure work as a strategy to improve vitamin D status in the elderly: a cluster randomised controlled trial

.

Osteoporos Int

23

:

615

–

624

254

Larsen

ER

,

Mosekilde

L

,

Foldspang

A

2005

Vitamin D and calcium supplementation prevents severe falls in elderly community-dwelling women: a pragmatic population-based 3-year intervention study

.

Aging Clin Exp Res

17

:

125

–

132

255

Flicker

L

,

MacInnis

RJ

,

Stein

MS

,

Scherer

SC

,

Mead

KE

,

Nowson

CA

,

Thomas

J

,

Lowndes

C

,

Hopper

JL

,

Wark

JD

2005

Should older people in residential care receive vitamin D to prevent falls? Results of a randomized trial

.

J Am Geriatr Soc

53

:

1881

–

1888

256

Bischoff-Ferrari

HA

,

Orav

EJ

,

Dawson-Hughes

B

2006

Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: a 3-year randomized controlled trial

.

Arch Intern Med

166

:

424

–

430

257

Dawson-Hughes

B

,

Harris

SS

,

Krall

EA

,

Dallal

GE

1997

Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older

.

N Engl J Med

337

:

670

–

676

258

Pfeifer

M

,

Begerow

B

,

Minne

HW

,

Suppan

K

,

Fahrleitner-Pammer

A

,

Dobnig

H

2009

Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals

.

Osteoporos Int

20

:

315

–

322

259

Bischoff

HA

,

Stähelin

HB

,

Dick

W

,

Akos

R

,

Knecht

M

,

Salis

C

,

Nebiker

M

,

Theiler

R

,

Pfeifer

M

,

Begerow

B

,

Lew

RA

,

Conzelmann

M

2003

Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial

.

J Bone Miner Res

18

:

343

–

351

260

Prince

RL

,

Austin

N

,

Devine

A

,

Dick

IM

,

Bruce

D

,

Zhu

K

2008

Effects of ergocalciferol added to calcium on the risk of falls in elderly high-risk women

.

Arch Intern Med

168

:

103

–

108

261

Pfeifer

M

,

Begerow

B

,

Minne

HW

,

Abrams

C

,

Nachtigall

D

,

Hansen

C

2000

Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women

.

J Bone Miner Res

15

:

1113

–

1118

262

Pfeifer

M

,

Begerow

B

,

Minne

HW

,

Schlotthauer

T

,

Pospeschill

M

,

Scholz

M

,

Lazarescu

AD

,

Pollähne

W

2001

Vitamin D status, trunk muscle strength, body sway, falls, and fractures among 237 postmenopausal women with osteoporosis

.

Exp Clin Endocrinol Diabetes

109

:

87

–

92

263

Graafmans

WC

,

Ooms

ME

,

Hofstee

HM

,

Bezemer

PD

,

Bouter

LM

,

Lips

P

1996

Falls in the elderly: a prospective study of risk factors and risk profiles

.

Am J Epidemiol

143

:

1129

–

1136

264

Broe

KE

,

Chen

TC

,

Weinberg

J

,

Bischoff-Ferrari

HA

,

Holick

MF

,

Kiel

DP

2007

A higher dose of vitamin D reduces the risk of falls in nursing home residents: a randomized, multiple-dose study

.

J Am Geriatr Soc

55

:

234

–

239

265

Grant

AM

,

Avenell

A

,

Campbell

MK

,

McDonald

AM

,

MacLennan

GS

,

McPherson

GC

,

Anderson

FH

,

Cooper

C

,

Francis

RM

,

Donaldson

C

,

Gillespie

WJ

,

Robinson

CM

,

Torgerson

DJ

,

Wallace

WA

2005

Oral vitamin D₃ and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial

.

Lancet

365

:

1621

–

1628

266

Porthouse

J

,

Cockayne

S

,

King

C

,

Saxon

L

,

Steele

E

,

Aspray

T

,

Baverstock

M

,

Birks

Y

,

Dumville

J

,

Francis

R

,

Iglesias

C

,

Puffer

S

,

Sutcliffe

A

,

Watt

I

,

Torgerson

DJ

2005

Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D₃) for prevention of fractures in primary care

.

BMJ

330

:

1003

267

Sanders

KM

,

Stuart

AL

,

Williamson

EJ

,

Simpson

JA

,

Kotowicz

MA

,

Young

D

,

Nicholson

GC

2010

Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial

.

JAMA

303

:

1815

–

1822

268

Smith

H

,

Anderson

F

,

Raphael

H

,

Maslin

P

,

Crozier

S

,

Cooper

C

2007

Effect of annual intramuscular vitamin D on fracture risk in elderly men and women: a population-based, randomized, double-blind, placebo-controlled trial

.

Rheumatology (Oxford)

46

:

1852

–

1857

269

Bischoff-Ferrari

HA

,

Dawson-Hughes

B

,

Willett

WC

,

Staehelin

HB

,

Bazemore

MG

,

Zee

RY

,

Wong

JB

2004

Effect of Vitamin D on falls: a meta-analysis

.

JAMA

291

:

1999

–

2006

270

Jackson

C

,

Gaugris

S

,

Sen

SS

,

Hosking

D

2007

The effect of cholecalciferol (vitamin D₃) on the risk of fall and fracture: a meta-analysis

.

QJM

100

:

185

–

192

271

Kalyani

RR

,

Stein

B

,

Valiyil

R

,

Manno

R

,

Maynard

JW

,

Crews

DC

2010

Vitamin D treatment for the prevention of falls in older adults: systematic review and meta-analysis

.

J Am Geriatr Soc

58

:

1299

–

1310

272

Richy

F

,

Dukas

L

,

Schacht

E

2008

Differential effects of D-hormone analogs and native vitamin D on the risk of falls: a comparative meta-analysis

.

Calcif Tissue Int

82

:

102

–

107

273

Boxer

RS

,

Dauser

DA

,

Walsh

SJ

,

Hager

WD

,

Kenny

AM

2008

The association between vitamin D and inflammation with the 6-minute walk and frailty in patients with heart failure

.

J Am Geriatr Soc

56

:

454

–

461

274

Mastaglia

SR

,

Seijo

M

,

Muzio

D

,

Somoza

J

,

Nuñez

M

,

Oliveri

B

2011

Effect of vitamin D nutritional status on muscle function and strength in healthy women aged over sixty-five years

.

J Nutr Health Aging

15

:

349

–

354

275

Houston

DK

,

Cesari

M

,

Ferrucci

L

,

Cherubini

A

,

Maggio

D

,

Bartali

B

,

Johnson

MA

,

Schwartz

GG

,

Kritchevsky

SB

2007

Association between vitamin D status and physical performance: the InCHIANTI study

.

J Gerontol A Biol Sci Med Sci

62

:

440

–

446

276

Annweiler

C

,

Schott

AM

,

Berrut

G

,

Fantino

B

,

Beauchet

O

2009

Vitamin D-related changes in physical performance: a systematic review

.

J Nutr Health Aging

13

:

893

–

898

277

Bischoff

HA

,

Stahelin

HB

,

Urscheler

N

,

Ehrsam

R

,

Vonthein

R

,

Perrig-Chiello

P

,

Tyndall

A

,

Theiler

R

1999

Muscle strength in the elderly: its relation to vitamin D metabolites

.

Arch Phys Med Rehabil

80

:

54

–

58

278

Bischoff-Ferrari

HA

,

Dietrich

T

,

Orav

EJ

,

Hu

FB

,

Zhang

Y

,

Karlson

EW

,

Dawson-Hughes

B

2004

Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged ≥60 y

.

Am J Clin Nutr

80

:

752

–

758

279

Wicherts

IS

,

van Schoor

NM

,

Boeke

AJ

,

Visser

M

,

Deeg

DJ

,

Smit

J

,

Knol

DL

,

Lips

P

2007

Vitamin D status predicts physical performance and its decline in older persons

.

J Clin Endocrinol Metab

92

:

2058

–

2065

280

Visser

M

,

Deeg

DJ

,

Lips

P

2003

Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam

.

J Clin Endocrinol Metab

88

:

5766

–

5772

281

Dam

TT

,

von Mühlen

D

,

Barrett-Connor

EL

2009

Sex-specific association of serum vitamin D levels with physical function in older adults

.

Osteoporos Int

20

:

751

–

760

282

Chan

R

,

Chan

D

,

Woo

J

,

Ohlsson

C

,

Mellström

D

,

Kwok

T

,

Leung

PC

2012

Not all elderly people benefit from vitamin D supplementation with respect to physical function: results from the osteoporotic fractures in men study, Hong Kong

.

J Am Geriatr Soc

60

:

290

–

295

283

Bunout

D

,

Barrera

G

,

Leiva

L

,

Gattas

V

,

de la Maza

MP

,

Avendaño

M

,

Hirsch

S

2006

Effects of vitamin D supplementation and exercise training on physical performance in Chilean vitamin D deficient elderly subjects

.

Exp Gerontol

41

:

746

–

752

284

Dhesi

JK

,

Jackson

SH

,

Bearne

LM

,

Moniz

C

,

Hurley

MV

,

Swift

CG

,

Allain

TJ

2004

Vitamin D supplementation improves neuromuscular function in older people who fall

.

Age Ageing

33

:

589

–

595

285

Moreira-Pfrimer

LD

,

Pedrosa

MA

,

Teixeira

L

,

Lazaretti-Castro

M

2009

Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: a randomized double-blind controlled trial

.

Ann Nutr Metab

54

:

291

–

300

286

Zhu

K

,

Austin

N

,

Devine

A

,

Bruce

D

,

Prince

RL

2010

A randomized controlled trial of the effects of vitamin D on muscle strength and mobility in older women with vitamin D insufficiency

.

J Am Geriatr Soc

58

:

2063

–

2068

287

Ward

KA

,

Das

G

,

Roberts

SA

,

Berry

JL

,

Adams

JE

,

Rawer

R

,

Mughal

MZ

2010

A randomized, controlled trial of vitamin D supplementation upon musculoskeletal health in postmenarchal females

.

J Clin Endocrinol Metab

95

:

4643

–

4651

288

Songpatanasilp

T

,

Chailurkit

LO

,

Nichachotsalid

A

,

Chantarasorn

M

2009

Combination of alfacalcidol with calcium can improve quadriceps muscle strength in elderly ambulatory Thai women who have hypovitaminosis D: a randomized controlled trial

.

J Med Assoc Thai

92

(

Suppl 5

):

S30

–

S41

289

Janssen

HC

,

Samson

MM

,

Verhaar

HJ

2010

Muscle strength and mobility in vitamin D-insufficient female geriatric patients: a randomized controlled trial on vitamin D and calcium supplementation

.

Aging Clin Exp Res

22

:

78

–

84

290

Glendenning

P

,

Zhu

K

,

Inderjeeth

C

,

Howat

P

,

Lewis

JR

,

Prince

RL

28

September

2011

Effects of three monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility and muscle strength in older postmenopausal women: a randomised controlled trial

.

J Bone Miner Res

291

Latham

NK

,

Anderson

CS

,

Lee

A

,

Bennett

DA

,

Moseley

A

,

Cameron

ID

2003

A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: the Frailty Interventions Trial in Elderly Subjects (FITNESS)

.

J Am Geriatr Soc

51

:

291

–

299

292

Corless

D

,

Dawson

E

,

Fraser

F

,

Ellis

M

,

Evans

SJ

,

Perry

JD

,

Reisner

C

,

Silver

CP

,

Beer

M

,

Boucher

BJ

, et al.

1985

Do vitamin D supplements improve the physical capabilities of elderly hospital patients?

Age Ageing

14

:

76

–

84

293

Kukuljan

S

,

Nowson

CA

,

Sanders

K

,

Daly

RM

2009

Effects of resistance exercise and fortified milk on skeletal muscle mass, muscle size, and functional performance in middle-aged and older men: an 18-mo randomized controlled trial

.

J Appl Physiol

107

:

1864

–

1873

294

Grady

D

,

Halloran

B

,

Cummings

S

,

Leveille

S

,

Wells

L

,

Black

D

,

Byl

N

1991

1,25-Dihydroxyvitamin D₃ and muscle strength in the elderly: a randomized controlled trial

.

J Clin Endocrinol Metab

73

:

1111

–

1117

295

El-Hajj Fuleihan

G

,

Nabulsi

M

,

Tamim

H

,

Maalouf

J

,

Salamoun

M

,

Khalife

H

,

Choucair

M

,

Arabi

A

,

Vieth

R

2006

Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial

.

J Clin Endocrinol Metab

91

:

405

–

412

296

Rejnmark

L

2011

Effects of vitamin D on muscle function and performance: a review of evidence from randomized controlled trials

.

Ther Adv Chronic Dis

2

:

25

–

37

297

Muir

SW

,

Montero-Odasso

M

2011

Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis

.

J Am Geriatr Soc

59

:

2291

–

2300

298

Lazaro

RP

,

Kirshner

HS

1980

Proximal muscle weakness in uremia. Case reports and review of the literature

.

Arch Neurol

37

:

555

–

558

299

Dastur

DK

,

Gagrat

BM

,

Wadia

NH

,

Desai

M

,

Bharucha

EP

1975

Nature of muscular change in osteomalacia: light- and electron-microscope observations

.

J Pathol

117

:

211

–

228

300

Yoshikawa

S

,

Nakamura

T

,

Tanabe

H

,

Imamura

T

1979

Osteomalacic myopathy

.

Endocrinol Jpn

26

:

65

–

72

301

Sorensen

OH

,

Lund

B

,

Saltin

B

,

Andersen

RB

,

Hjorth

L

,

Melsen

F

,

Mosekilde

L

1979

Myopathy in bone loss of ageing: improvement by treatment with 1α-hydroxycholecalciferol and calcium

.

Clin Sci (Lond)

56

:

157

–

161

302

Young

A

,

Brenton

DP

,

Edwards

R

1978

Analysis of muscle weakness in osteomalacia

.

Clin Sci Mol Med

54

:

31

303

Gilsanz

V

,

Kremer

A

,

Mo

AO

,

Wren

TA

,

Kremer

R

2010

Vitamin D status and its relation to muscle mass and muscle fat in young women

.

J Clin Endocrinol Metab

95

:

1595

–

1601

304

Oh

JH

,

Kim

SH

,

Kim

JH

,

Shin

YH

,

Yoon

JP

,

Oh

CH

2009

The level of vitamin D in the serum correlates with fatty degeneration of the muscles of the rotator cuff

.

J Bone Joint Surg Br

91

:

1587

–

1593

305

Tagliafico

AS

,

Ameri

P

,

Bovio

M

,

Puntoni

M

,

Capaccio

E

,

Murialdo

G

,

Martinoli

C

2010

Relationship between fatty degeneration of thigh muscles and vitamin D status in the elderly: a preliminary MRI study

.

AJR Am J Roentgenol

194

:

728

–

734

306

Marantes

I

,

Achenbach

SJ

,

Atkinson

EJ

,

Khosla

S

,

Melton

LJ

,

Amin

S

2011

Is vitamin D a determinant of muscle mass and strength?

J Bone Miner Res

26

:

2860

–

2871

307

Gordon

PL

,

Doyle

JW

,

Johansen

KL

2012

Association of 1,25-dihydroxyvitamin D levels with physical performance and thigh muscle cross-sectional area in chronic kidney disease stage 3 and 4

.

J Ren Nutr

22

:

423

–

433

308

Ducher

G

,

Kukuljan

S

,

Hill

B

,

Garnham

AP

,

Nowson

CA

,

Kimlin

MG

,

Cook

J

2011

Vitamin D status and musculoskeletal health in adolescent male ballet dancers a pilot study

.

J Dance Med Sci

15

:

99

–

107

309

Nigro

J

,

Osman

N

,

Dart

AM

,

Little

PJ

2006

Insulin resistance and atherosclerosis

.

Endocr Rev

27

:

242

–

259

310

Pinelli

NR

,

Jaber

LA

,

Brown

MB

,

Herman

WH

2010

Serum 25-hydroxy vitamin D and insulin resistance, metabolic syndrome, and glucose intolerance among Arab Americans

.

Diabetes Care

33

:

1373

–

1375

311

Liu

E

,

Meigs

JB

,

Pittas

AG

,

McKeown

NM

,

Economos

CD

,

Booth

SL

,

Jacques

PF

2009

Plasma 25-hydroxyvitamin D is associated with markers of the insulin resistant phenotype in nondiabetic adults

.

J Nutr

139

:

329

–

334

312

Kayaniyil

S

,

Vieth

R

,

Retnakaran

R

,

Knight

JA

,

Qi

Y

,

Gerstein

HC

,

Perkins

BA

,

Harris

SB

,

Zinman

B

,

Hanley

AJ

2010

Association of vitamin D with insulin resistance and β-cell dysfunction in subjects at risk for type 2 diabetes

.

Diabetes Care

33

:

1379

–

1381

313

Ford

ES

,

Zhao

G

,

Tsai

J

,

Li

C

2011

Associations between concentrations of vitamin D and concentrations of insulin, glucose, and HbA1c among adolescents in the United States

.

Diabetes Care

34

:

646

–

648

314

Muscogiuri

G

,

Sorice

GP

,

Prioletta

A

,

Policola

C

,

Della Casa

S

,

Pontecorvi

A

,

Giaccari

A

2010

25-Hydroxyvitamin D concentration correlates with insulin-sensitivity and BMI in obesity

.

Obesity (Silver Spring)

18

:

1906

–

1910

315

Del Gobbo

LC

,

Song

Y

,

Dannenbaum

DA

,

Dewailly

E

,

Egeland

GM

2011

Serum 25-hydroxyvitamin D is not associated with insulin resistance or β-cell function in Canadian Cree

.

J Nutr

141

:

290

–

295

316

Gannagé-Yared

MH

,

Chedid

R

,

Khalife

S

,

Azzi

E

,

Zoghbi

F

,

Halaby

G

2009

Vitamin D in relation to metabolic risk factors, insulin sensitivity and adiponectin in a young Middle-Eastern population

.

Eur J Endocrinol

160

:

965

–

971

317

Chiu

KC

,

Chu

A

,

Go

VL

,

Saad

MF

2004

Hypovitaminosis D is associated with insulin resistance and β-cell dysfunction

.

Am J Clin Nutr

79

:

820

–

825

318

Scragg

R

,

Sowers

M

,

Bell

C

2004

Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey

.

Diabetes Care

27

:

2813

–

2818

319

Cheng

S

,

Massaro

JM

,

Fox

CS

,

Larson

MG

,

Keyes

MJ

,

McCabe

EL

,

Robins

SJ

,

O'Donnell

CJ

,

Hoffmann

U

,

Jacques

PF

,

Booth

SL

,

Vasan

RS

,

Wolf

M

,

Wang

TJ

2010

Adiposity, cardiometabolic risk, and vitamin D status: the Framingham Heart Study

.

Diabetes

59

:

242

–

248

320

McGill

AT

,

Stewart

JM

,

Lithander

FE

,

Strik

CM

,

Poppitt

SD

2008

Relationships of low serum vitamin D₃ with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity

.

Nutr J

7

:

4

321

Manco

M

,

Calvani

M

,

Nanni

G

,

Greco

AV

,

Iaconelli

A

,

Gasbarrini

G

,

Castagneto

M

,

Mingrone

G

2005

Low 25-hydroxyvitamin D does not affect insulin sensitivity in obesity after bariatric surgery

.

Obes Res

13

:

1692

–

1700

322

Taylor

WH

,

Khaleeli

AA

2001

Coincident diabetes mellitus and primary hyperparathyroidism

.

Diabetes Metab Res Rev

17

:

175

–

180

323

Kamycheva

E

,

Jorde

R

,

Figenschau

Y

,

Haug

E

2007

Insulin sensitivity in subjects with secondary hyperparathyroidism and the effect of a low serum 25-hydroxyvitamin D level on insulin sensitivity

.

J Endocrinol Invest

30

:

126

–

132

324

Kayaniyil

S

,

Vieth

R

,

Harris

SB

,

Retnakaran

R

,

Knight

JA

,

Gerstein

HC

,

Perkins

BA

,

Zinman

B

,

Hanley

AJ

2011

Association of 25(OH)D and PTH with metabolic syndrome and its traditional and nontraditional components

.

J Clin Endocrinol Metab

96

:

168

–

175

325

Isaia

G

,

Giorgino

R

,

Adami

S

2001

High prevalence of hypovitaminosis D in female type 2 diabetic population

.

Diabetes Care

24

:

1496

326

Tahrani

AA

,

Ball

A

,

Shepherd

L

,

Rahim

A

,

Jones

AF

,

Bates

A

2010

The prevalence of vitamin D abnormalities in South Asians with type 2 diabetes mellitus in the UK

.

Int J Clin Pract

64

:

351

–

355

327

Brock

KE

,

Huang

WY

,

Fraser

DR

,

Ke

L

,

Tseng

M

,

Mason

RS

,

Stolzenberg-Solomon

RZ

,

Freedman

DM

,

Ahn

J

,

Peters

U

,

McCarty

C

,

Hollis

BW

,

Ziegler

RG

,

Purdue

MP

,

Graubard

BI

2011

Diabetes prevalence is associated with serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in US middle-aged Caucasian men and women: a cross-sectional analysis within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

.

Br J Nutr

106

:

339

–

344

328

Scragg

R

,

Holdaway

I

,

Singh

V

,

Metcalf

P

,

Baker

J

,

Dryson

E

1995

Serum 25-hydroxyvitamin D₃ levels decreased in impaired glucose tolerance and diabetes mellitus

.

Diabetes Res Clin Pract

27

:

181

–

188

329

Nimitphong

H

,

Chanprasertyothin

S

,

Jongjaroenprasert

W

,

Ongphiphadhanakul

B

2009

The association between vitamin D status and circulating adiponectin independent of adiposity in subjects with abnormal glucose tolerance

.

Endocrine

36

:

205

–

210

330

Wareham

NJ

,

Byrne

CD

,

Carr

C

,

Day

NE

,

Boucher

BJ

,

Hales

CN

1997

Glucose intolerance is associated with altered calcium homeostasis: a possible link between increased serum calcium concentration and cardiovascular disease mortality

.

Metabolism

46

:

1171

–

1177

331

Al-Daghri

NM

,

Al-Attas

OS

,

Al-Okail

MS

,

Alkharfy

KM

,

Al-Yousef

MA

,

Nadhrah

HM

,

Sabico

SB

,

Chrousos

GP

2010

Severe hypovitaminosis D is widespread and more common in non-diabetics than diabetics in Saudi adults

.

Saudi Med J

31

:

775

–

780

332

Forouhi

NG

,

Luan

J

,

Cooper

A

,

Boucher

BJ

,

Wareham

NJ

2008

Baseline serum 25-hydroxy vitamin D is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990–2000

.

Diabetes

57

:

2619

–

2625

333

Gagnon

C

,

Lu

ZX

,

Magliano

DJ

,

Dunstan

DW

,

Shaw

JE

,

Zimmet

PZ

,

Sikaris

K

,

Grantham

N

,

Ebeling

PR

,

Daly

RM

2011

Serum 25-hydroxyvitamin D, calcium intake, and risk of type 2 diabetes after 5 years: results from a national, population-based prospective study (the Australian Diabetes, Obesity and Lifestyle study)

.

Diabetes Care

34

:

1133

–

1138

334

Pittas

AG

,

Dawson-Hughes

B

,

Li

T

,

Van Dam

RM

,

Willett

WC

,

Manson

JE

,

Hu

FB

2006

Vitamin D and calcium intake in relation to type 2 diabetes in women

.

Diabetes Care

29

:

650

–

656

335

Liu

S

,

Song

Y

,

Ford

ES

,

Manson

JE

,

Buring

JE

,

Ridker

PM

2005

Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women

.

Diabetes Care

28

:

2926

–

2932

336

Pittas

AG

,

Nelson

J

,

Mitri

J

,

Hillmann

W

,

Garganta

C

,

Nathan

D

,

Hu

FB

,

Dawson-Hughes

B

;

Diabetes Prevention Program Research Group

2012

Plasma 25-hydroxyvitamin D and progression to diabetes in patients at risk for diabetes: an ancillary analysis in the Diabetes Prevention Program

.

Diabetes Care

35

:

565

–

573

337

Robinson

JG

,

Manson

JE

,

Larson

J

,

Liu

S

,

Song

Y

,

Howard

BV

,

Phillips

L

,

Shikany

JM

,

Allison

M

,

Curb

JD

,

Johnson

KC

,

Watts

N

2011

Lack of association between 25(OH)D levels and incident type 2 diabetes in older women

.

Diabetes Care

34

:

628

–

634

338

Grimnes

G

,

Emaus

N

,

Joakimsen

RM

,

Figenschau

Y

,

Jenssen

T

,

Njølstad

I

,

Schirmer

H

,

Jorde

R

2010

Baseline serum 25-hydroxyvitamin D concentrations in the Tromso Study 1994–95 and risk of developing type 2 diabetes mellitus during 11 years of follow-up

.

Diabet Med

27

:

1107

–

1115

339

Mattila

C

,

Knekt

P

,

Männistö

S

,

Rissanen

H

,

Laaksonen

MA

,

Montonen

J

,

Reunanen

A

2007

Serum 25-hydroxyvitamin D concentration and subsequent risk of type 2 diabetes

.

Diabetes Care

30

:

2569

–

2570

340

Nilas

L

,

Christiansen

C

1984

Treatment with vitamin D or its analogues does not change body weight or blood glucose level in postmenopausal women

.

Int J Obes

8

:

407

–

411

341

Fliser

D

,

Stefanski

A

,

Franek

E

,

Fode

P

,

Gudarzi

A

,

Ritz

E

1997

No effect of calcitriol on insulin-mediated glucose uptake in healthy subjects

.

Eur J Clin Invest

27

:

629

–

633

342

Mitri

J

,

Dawson-Hughes

B

,

Hu

FB

,

Pittas

AG

2011

Effects of vitamin D and calcium supplementation on pancreatic β-cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial

.

Am J Clin Nutr

94

:

486

–

494

343

Nagpal

J

,

Pande

JN

,

Bhartia

A

2009

A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D₃ supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men

.

Diabet Med

26

:

19

–

27

344

Pittas

AG

,

Harris

SS

,

Stark

PC

,

Dawson-Hughes

B

2007

The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in non-diabetic adults

.

Diabetes Care

30

:

980

–

986

345

von Hurst

PR

,

Stonehouse

W

,

Coad

J

2010

Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient: a randomised, placebo-controlled trial

.

Br J Nutr

103

:

549

–

555

346

Nikooyeh

B

,

Neyestani

TR

,

Farvid

M

,

Alavi-Majd

H

,

Houshiarrad

A

,

Kalayi

A

,

Shariatzadeh

N

,

Gharavi

A

,

Heravifard

S

,

Tayebinejad

N

,

Salekzamani

S

,

Zahedirad

M

2011

Daily consumption of vitamin D- or vitamin D + calcium-fortified yogurt drink improved glycemic control in patients with type 2 diabetes: a randomized clinical trial

.

Am J Clin Nutr

93

:

764

–

771

347

Borissova

AM

,

Tankova

T

,

Kirilov

G

,

Dakovska

L

,

Kovacheva

R

2003

The effect of vitamin D₃ on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients

.

Int J Clin Pract

57

:

258

–

261

348

Orwoll

E

,

Riddle

M

,

Prince

M

1994

Effects of vitamin D on insulin and glucagon secretion in non-insulin-dependent diabetes mellitus

.

Am J Clin Nutr

59

:

1083

–

1087

349

Parekh

D

,

Sarathi

V

,

Shivane

VK

,

Bandgar

TR

,

Menon

PS

,

Shah

NS

2010

Pilot study to evaluate the effect of short-term improvement in vitamin D status on glucose tolerance in patients with type 2 diabetes mellitus

.

Endocr Pract

16

:

600

–

608

350

Jorde

R

,

Figenschau

Y

2009

Supplementation with cholecalciferol does not improve glycaemic control in diabetic subjects with normal serum 25-hydroxyvitamin D levels

.

Eur J Nutr

48

:

349

–

354

351

Taylor

AV

,

Wise

PH

1998

Vitamin D replacement in Asians with diabetes may increase insulin resistance

.

Postgrad Med J

74

:

365

–

366

352

Mitri

J

,

Muraru

MD

,

Pittas

AG

2011

Vitamin D and type 2 diabetes: a systematic review

.

Eur J Clin Nutr

65

:

1005

–

1015

353

Schiaffino

S

2010

Fibre types in skeletal muscle: a personal account

.

Acta Physiol (Oxf)

199

:

451

–

463

354

Spangenburg

EE

,

Booth

FW

2003

Molecular regulation of individual skeletal muscle fibre types

.

Acta Physiol Scand

178

:

413

–

424

355

Neville

PF

,

DeLuca

HF

1966

The synthesis of [1,2–3H]vitamin D₃ and the tissue localization of a 0.25-mu-g (10 IU) dose per rat

.

Biochemistry

5

:

2201

–

2207

356

Stumpf

WE

,

Sar

M

,

Reid

FA

,

Tanaka

Y

,

DeLuca

HF

1979

Target cells for 1,25-dihydroxyvitamin D₃ in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid

.

Science

206

:

1188

–

1190

357

Boland

R

,

Norman

A

,

Ritz

E

,

Hasselbach

W

1985

Presence of a 1,25-dihydroxy-vitamin D₃ receptor in chick skeletal muscle myoblasts

.

Biochem Biophys Res Commun

128

:

305

–

311

358

Sandgren

ME

,

Brönnegärd

M

,

DeLuca

HF

1991

Tissue distribution of the 1,25-dihydroxyvitamin D₃ receptor in the male rat

.

Biochem Biophys Res Commun

181

:

611

–

616

359

Barr

R

,

Macdonald

H

,

Stewart

A

,

McGuigan

F

,

Rogers

A

,

Eastell

R

,

Felsenberg

D

,

Glüer

C

,

Roux

C

,

Reid

DM

2010

Association between vitamin D receptor gene polymorphisms, falls, balance and muscle power: results from two independent studies (APOSS and OPUS)

.

Osteoporos Int

21

:

457

–

466

360

Oh

JY

,

Barrett-Connor

E

2002

Association between vitamin D receptor polymorphism and type 2 diabetes or metabolic syndrome in community-dwelling older adults: the Rancho Bernardo Study

.

Metabolism

51

:

356

–

359

361

Ortlepp

JR

,

Metrikat

J

,

Albrecht

M

,

von Korff

A

,

Hanrath

P

,

Hoffmann

R

2003

The vitamin D receptor gene variant and physical activity predicts fasting glucose levels in healthy young men

.

Diabet Med

20

:

451

–

454

362

Malecki

MT

,

Frey

J

,

Moczulski

D

,

Klupa

T

,

Kozek

E

,

Sieradzki

J

2003

Vitamin D receptor gene polymorphisms and association with type 2 diabetes mellitus in a Polish population

.

Exp Clin Endocrinol Diabetes

111

:

505

–

509

363

Ye

WZ

,

Reis

AF

,

Dubois-Laforgue

D

,

Bellanné-Chantelot

C

,

Timsit

J

,

Velho

G

2001

Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset

.

Eur J Endocrinol

145

:

181

–

186

364

Bid

HK

,

Konwar

R

,

Aggarwal

CG

,

Gautam

S

,

Saxena

M

,

Nayak

VL

,

Banerjee

M

2009

Vitamin D receptor (FokI, BsmI and TaqI) gene polymorphisms and type 2 diabetes mellitus: a North Indian study

.

Indian J Med Sci

63

:

187

–

194

365

Speer

G

,

Cseh

K

,

Winkler

G

,

Vargha

P

,

Braun

E

,

Takács

I

,

Lakatos

P

2001

Vitamin D and estrogen receptor gene polymorphisms in type 2 diabetes mellitus and in android type obesity

.

Eur J Endocrinol

144

:

385

–

389

366

Filus

A

,

Trzmiel

A

,

Kuliczkowska-Płaksej

J

,

Tworowska

U

,

Jedrzejuk

D

,

Milewicz

A

,

Medraœ

M

2008

Relationship between vitamin D receptor BsmI and FokI polymorphisms and anthropometric and biochemical parameters describing metabolic syndrome

.

Aging Male

11

:

134

–

139

367

Faulkner

KA

,

Cauley

JA

,

Zmuda

JM

,

Landsittel

DP

,

Newman

AB

,

Studenski

SA

,

Redfern

MS

,

Ensrud

KE

,

Fink

HA

,

Lane

NE

,

Nevitt

MC

2006

Higher 1,25-dihydroxyvitamin D₃ concentrations associated with lower fall rates in older community-dwelling women

.

Osteoporos Int

17

:

1318

–

1328

368

Verreault

R

,

Semba

RD

,

Volpato

S

,

Ferrucci

L

,

Fried

LP

,

Guralnik

JM

2002

Low serum vitamin D does not predict new disability or loss of muscle strength in older women

.

J Am Geriatr Soc

50

:

912

–

917

369

Arden

NK

,

Crozier

S

,

Smith

H

,

Anderson

F

,

Edwards

C

,

Raphael

H

,

Cooper

C

2006

Knee pain, knee osteoarthritis, and the risk of fracture

.

Arthritis Rheum

55

:

610

–

615

370

Law

M

,

Withers

H

,

Morris

J

,

Anderson

F

2006

Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation

.

Age Ageing

35

:

482

–

486

371

Chapuy

MC

,

Arlot

ME

,

Duboeuf

F

,

Brun

J

,

Crouzet

B

,

Arnaud

S

,

Delmas

PD

,

Meunier

PJ

1992

Vitamin D₃ and calcium to prevent hip fractures in the elderly women

.

N Engl J Med

327

:

1637

–

1642

372

Chapuy

MC

,

Pamphile

R

,

Paris

E

,

Kempf

C

,

Schlichting

M

,

Arnaud

S

,

Garnero

P

,

Meunier

PJ

2002

Combined calcium and vitamin D₃ supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study

.

Osteoporos Int

13

:

257

–

264

373

Gallagher

JC

,

Rapuri

PB

,

Smith

LM

2007

An age-related decrease in creatinine clearance is associated with an increase in number of falls in untreated women but not in women receiving calcitriol treatment

.

J Clin Endocrinol Metab

92

:

51

–

58

374

Dukas

L

,

Bischoff

HA

,

Lindpaintner

LS

,

Schacht

E

,

Birkner-Binder

D

,

Damm

TN

,

Thalmann

B

,

Stähelin

HB

2004

Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily

.

J Am Geriatr Soc

52

:

230

–

236

375

Burleigh

E

,

McColl

J

,

Potter

J

2007

Does vitamin D stop inpatients falling? A randomised controlled trial

.

Age Ageing

36

:

507

–

513

376

Berggren

M

,

Stenvall

M

,

Olofsson

B

,

Gustafson

Y

2008

Evaluation of a fall-prevention program in older people after femoral neck fracture: a one-year follow-up

.

Osteoporos Int

19

:

801

–

809

377

Harwood

RH

,

Sahota

O

,

Gaynor

K

,

Masud

T

,

Hosking

DJ

2004

A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study

.

Age Ageing

33

:

45

–

51

378

Sato

Y

,

Manabe

S

,

Kuno

H

,

Oizumi

K

1999

Amelioration of osteopenia and hypovitaminosis D by 1α-hydroxyvitamin D₃ in elderly patients with Parkinson's disease

.

J Neurol Neurosurg Psychiatry

66

:

64

–

68

379

Gerdhem

P

,

Ringsberg

KA

,

Obrant

KJ

,

Akesson

K

2005

Association between 25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of Elderly Women

.

Osteoporos Int

16

:

1425

–

1431

380

Annweiler

C

,

Beauchet

O

,

Berrut

G

,

Fantino

B

,

Bonnefoy

M

,

Herrmann

FR

,

Schott

AM

2009

Is there an association between serum 25-hydroxyvitamin D concentration and muscle strength among older women? Results from baseline assessment of the EPIDOS study

.

J Nutr Health Aging

13

:

90

–

95

381

Beauchet

O

,

Annweiler

C

,

Verghese

J

,

Fantino

B

,

Herrmann

FR

,

Allali

G

2011

Biology of gait control: vitamin D involvement

.

Neurology

76

:

1617

–

1622

382

Mowé

M

,

Haug

E

,

Bøhmer

T

1999

Low serum calcidiol concentration in older adults with reduced muscular function

.

J Am Geriatr Soc

47

:

220

–

226

383

Brunner

RL

,

Cochrane

B

,

Jackson

RD

,

Larson

J

,

Lewis

C

,

Limacher

M

,

Rosal

M

,

Shumaker

S

,

Wallace

R

2008

Calcium, vitamin D supplementation, and physical function in the Women's Health Initiative

.

J Am Diet Assoc

108

:

1472

–

1479

384

Lips

P

,

Binkley

N

,

Pfeifer

M

,

Recker

R

,

Samanta

S

,

Cohn

DA

,

Chandler

J

,

Rosenberg

E

,

Papanicolaou

DA

2010

Once-weekly dose of 8400 IU vitamin D₃ compared with placebo: effects on neuromuscular function and tolerability in older adults with vitamin D insufficiency

.

Am J Clin Nutr

91

:

985

–

991

385

Johnson

KR

,

Jobber

J

,

Stonawski

BJ

1980

Prophylactic vitamin D in the elderly

.

Age Ageing

9

:

121

–

127

386

Witham

MD

,

Crighton

LJ

,

Gillespie

ND

,

Struthers

AD

,

McMurdo

ME

2010

The effects of vitamin D supplementation on physical function and quality of life in older patients with heart failure: a randomized controlled trial

.

Circ Heart Fail

3

:

195

–

201

387

Kenny

AM

,

Biskup

B

,

Robbins

B

,

Marcella

G

,

Burleson

JA

2003

Effects of vitamin D supplementation on strength, physical function, and health perception in older, community-dwelling men

.

J Am Geriatr Soc

51

:

1762

–

1767

388

Gupta

R

,

Sharma

U

,

Gupta

N

,

Kalaivani

M

,

Singh

U

,

Guleria

R

,

Jagannathan

NR

,

Goswami

R

2010

Effect of cholecalciferol and calcium supplementation on muscle strength and energy metabolism in vitamin D-deficient Asian Indians: a randomized, controlled trial

.

Clin Endocrinol (Oxf)

73

:

445

–

451

389

Gloth

FM

,

Smith

CE

,

Hollis

BW

,

Tobin

JD

1995

Functional improvement with vitamin D replenishment in a cohort of frail, vitamin D-deficient older people

.

J Am Geriatr Soc

43

:

1269

–

1271

390

Artaza

JN

,

Norris

KC

2009

Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells

.

J Endocrinol

200

:

207

–

221

Copyright © 2013 by The Endocrine Society

Cã¡Ch Sá»­ DụNg Vitamin D

Source: https://academic.oup.com/edrv/article/34/1/33/2354646