**2. Function of vitamin D**

Vitamin D is known for its crucial role in bone health about a century ago. However, it has also demonstrated its role and effectiveness in extra-skeletal roles of vitamin D during the past two decades [5].

#### **2.1 Vitamin D and bone health**

Vitamin D regulates physiological functions by controlling the metabolism of calcium and phosphates, stimulates growth, and promotes the necessary remodeling of bones and teeth [6]. Vitamin D deficiency is often associated with bone disorders (such as rickets, osteomalacia, and osteoporosis); when serum calcium decreases, the thyroid gland immediately releases parathyroid hormone (PTH),

which acts by stimulating bone reabsorption and reduction of calcium urinary excretion [7].

Vitamin D levels are positively correlated with bone mineral density (BMD) [4]. Many observational studies have reported relations between chronic lower vitamin D concentrations and poorer lower-extremity function, lower muscle strength, lower contraction speed, and lower appendicular muscle mass [8]. Vitamin D deficiency can put people at risk because of low bone mineral density, osteopenia, osteoporosis, and tooth loss [6].

#### **2.2 Vitamin D and non-skeletal diseases**

Observational studies have shown associations between the low concentration of serum vitamin D and increased risk of cancer, cardiovascular diseases, disorders of glucose metabolism, neurodegenerative diseases, and mortality [3]. Vitamin D modulates a variety of processes and regulatory systems including host defense, inflammation, and immunity and repair, especially patients with lung diseases often have low vitamin D serum level [9].

The biological effect of vitamin D on cardiac function is through reduced remodeling and fibrosis secondary to negative regulation of renin by vitamin D receptor (VDR)-linked gene regulation and through reduced cardiac metalloproteinase activities [10]. In addition, many indications support a relation between hypovitaminosis D and slower nerve conduction and poorer executive functions [8]. VDR are also expressed on immune cells (T and B cells, monocytes/macrophages, mast cells, and antigen-presenting cells) [10]. Moreover, vitamin D may exert positive effects on oral health by affecting the production of antimicrobial peptides [6].

Furthermore, many studies have demonstrated that vitamin D supplementation has a beneficial effect in decreasing the mortality rate under multiple factors, by influencing the cardiovascular system, immune system, tumor progression, and others [11].
