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Vitamin D and extraskeletal health

Author
Roger Bouillon, MD, PhD, FRCP
Section Editor
Clifford J Rosen, MD
Deputy Editor
Jean E Mulder, MD

INTRODUCTION

Vitamin D deficiency was originally discovered as the cause of rickets due to lack of exposure to sunshine or vitamin D-rich food. This disease is still endemic in major parts of the world [1]. Subsequently, several meta-analyses showed that supplementation with vitamin D and calcium decreased the risk of osteoporotic fractures in older adults. The details of the protocols and overall results of the studies are reviewed separately.

In addition to its role in calcium and bone homeostasis, vitamin D potentially regulates many other cellular functions. The vitamin D receptor (VDR) is nearly universally expressed in nucleated cells. About 3 percent of the human/mouse genome is under the control of 1,25-dihydroxyvitamin D, the active form of vitamin D. Furthermore, at least 10 tissues outside the kidney express 1-alpha-hydroxylase (CYP27B1), the enzyme responsible for converting vitamin D to its active form, and therefore the active hormone can be generated in an auto or paracrine way. Thus, the spectrum of activity of the vitamin D endocrine system is much broader than calcium/bone homeostasis, and in this regard, the vitamin D-VDR system resembles that of other ligands of nuclear receptors, such as thyroid hormone [2-4].

This chapter will review the “extraskeletal” effects of vitamin D (deficiency), especially its effect on muscle function, cancer, and on the immune, cardiovascular, and metabolic system. The skeletal manifestations, causes, and treatment of vitamin D deficiency are discussed elsewhere. (See "Epidemiology and etiology of osteomalacia" and "Causes of vitamin D deficiency and resistance" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

MUSCLE FUNCTION

Muscle weakness — Observational studies suggest an association between poor vitamin D status (<10 or <20 ng/mL [<25 or <50 nmol/L]) and muscle weakness in children and older individuals [5-9]. However, a causal relationship between vitamin D supplementation and improvement in muscle weakness has not been clearly demonstrated in randomized trials, and the optimal 25-hydroxyvitamin D (25[OH]D) concentration for muscle function is unknown. Any benefit of vitamin D supplementation on muscle strength is likely to occur in patients with baseline 25(OH)D levels below 10 or 20 ng/mL (25 or 50 nmol/L).

There are several lines of evidence that suggest a relationship between vitamin D and muscle function [10]. Muscle from vitamin D receptor (VDR) null mice shows clear developmental abnormalities as immature muscle genes and proteins survive in VDR null but not wild type adult muscle [4]. In addition, striated muscle fibers are smaller in VDR null mice. Adult skeletal muscle, however, does not seems to express VDR protein when measured by highly specific antibodies [11], but VDR is expressed in muscle cell precursors or stem cells [4,10]. Children with hereditary vitamin D deficiency (ie, genetic CYP27B1 deficiency) who are deficient in the production of 1,25-dihydroxyvitamin D have profound muscle weakness, which vitamin D or 1,25-dihydroxyvitamin D therapy rapidly improves [4]. In addition, vitamin D supplementation improved muscle weakness and recovery of energy stores (maximal mitochondrial oxidative phosphorylation rate, as measured by in vivo magnetic resonance spectroscopy) after physical exercise in severely vitamin D-deficient but otherwise healthy adults [12].

                 

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