Vitamin D Metabolism and Deficiency

**3**

**Chapter 1**

**Abstract**

**1. Introduction**

Vitamin D Metabolism

present vitamin D synthesis and its action steps in detail.

**Keywords:** Vitamin D, Vitamin D characteristics

Vitamin D plays an important role in bone metabolism. Vitamin D is a group of biologically inactive, fat-soluble prohormones that exist in two major forms: ergocalciferol (vitamin D2) produced by plants in response to ultraviolet irradiation and cholecalciferol (vitamin D3) derived from animal tissues or 7-dehydrocholesterol in human skin by the action of ultraviolet rays present in sunlight. Vitamin D, which is biologically inactive, needs two-step hydroxylation for activation. All of these steps are of crucial for Vitamin D to show its effect properly. In this section, we will

Vitamin D plays an important role in calcium and phosphorus metabolism, which are essential for bone health and various biological functions. In vitamin D deficiency, clinical and biochemical rickets characterized by hypocalcemia (irritability, fatigue, muscle cramps, seizures), hypophosphatemia and skeletal manifestations (delayed closure of fontanelles, craniotabes, frontal bossing, bowed legs, enlarged wrists, bone pain, and short stature) in children and adolescents or osteomalacia in adults may occur. Over the past several decades, it has been reported that the efficiency of vitamin D is not limited only to maintaining bone health by managing the calcium homeostasis, but also seems to have anti-inflamatory, immunemodulating and pro-apopitothic properties [1]. There are two different precursor molecules of vitamin D. The first is vitamin D3, or cholecalciferol, which is the main source of vitamin D in the body and is synthesized from the skin by exposure to sun. Vitamin D3 can also be obtained from dietary animal foods (fish, egg yolks) or medicines (vitamin supplements). The second precursor is vitamin D2, or ergocalciferol, which can be used as a source of vitamin D via oral medication or through enriched foods. Vitamin D3 differs in molecular structure from vitamin D2 in that it has a double bond between the 22nd and 23rd carbon atoms and a methyl group on the 24th carbon atom [2]. These structural differences in vitamin D2 affect its catabolism. Compared to vitamin D3, vitamin D2 has a lower affinity for vitamin Dbinding protein (VDBP), which leads to its easy removal from the circulation, a reduced formation of 25-hydroxy vitamin D2 (25OHD2) by the 25-hydroxylase enzyme, and increased inactivation by the action of 24-hydroxylase [3–5]. Although both vitamin D2 and D3 are used as drugs, studies have shown that a higher serum 25OHD2 vitamin level is obtained when vitamin D3 is used in treatment compared to vitamin D2 [6]. In addition, it has been shown that active vitamin D obtained from vitamin D3 has a higher affinity for the vitamin D receptor (VDR) [4]. Despite these differences, vitamins D2 and D3 are both metabolized in substantially the

*Sezer Acar and Behzat Özkan*

## **Chapter 1** Vitamin D Metabolism

*Sezer Acar and Behzat Özkan*

### **Abstract**

Vitamin D plays an important role in bone metabolism. Vitamin D is a group of biologically inactive, fat-soluble prohormones that exist in two major forms: ergocalciferol (vitamin D2) produced by plants in response to ultraviolet irradiation and cholecalciferol (vitamin D3) derived from animal tissues or 7-dehydrocholesterol in human skin by the action of ultraviolet rays present in sunlight. Vitamin D, which is biologically inactive, needs two-step hydroxylation for activation. All of these steps are of crucial for Vitamin D to show its effect properly. In this section, we will present vitamin D synthesis and its action steps in detail.

**Keywords:** Vitamin D, Vitamin D characteristics

### **1. Introduction**

Vitamin D plays an important role in calcium and phosphorus metabolism, which are essential for bone health and various biological functions. In vitamin D deficiency, clinical and biochemical rickets characterized by hypocalcemia (irritability, fatigue, muscle cramps, seizures), hypophosphatemia and skeletal manifestations (delayed closure of fontanelles, craniotabes, frontal bossing, bowed legs, enlarged wrists, bone pain, and short stature) in children and adolescents or osteomalacia in adults may occur. Over the past several decades, it has been reported that the efficiency of vitamin D is not limited only to maintaining bone health by managing the calcium homeostasis, but also seems to have anti-inflamatory, immunemodulating and pro-apopitothic properties [1]. There are two different precursor molecules of vitamin D. The first is vitamin D3, or cholecalciferol, which is the main source of vitamin D in the body and is synthesized from the skin by exposure to sun. Vitamin D3 can also be obtained from dietary animal foods (fish, egg yolks) or medicines (vitamin supplements). The second precursor is vitamin D2, or ergocalciferol, which can be used as a source of vitamin D via oral medication or through enriched foods. Vitamin D3 differs in molecular structure from vitamin D2 in that it has a double bond between the 22nd and 23rd carbon atoms and a methyl group on the 24th carbon atom [2]. These structural differences in vitamin D2 affect its catabolism. Compared to vitamin D3, vitamin D2 has a lower affinity for vitamin Dbinding protein (VDBP), which leads to its easy removal from the circulation, a reduced formation of 25-hydroxy vitamin D2 (25OHD2) by the 25-hydroxylase enzyme, and increased inactivation by the action of 24-hydroxylase [3–5]. Although both vitamin D2 and D3 are used as drugs, studies have shown that a higher serum 25OHD2 vitamin level is obtained when vitamin D3 is used in treatment compared to vitamin D2 [6]. In addition, it has been shown that active vitamin D obtained from vitamin D3 has a higher affinity for the vitamin D receptor (VDR) [4]. Despite these differences, vitamins D2 and D3 are both metabolized in substantially the

same way and are commonly referred to as vitamin D. Vitamin D is a prohormone and inactive, and to be activated, it must go through a series of enzymatic and nonenzymatic steps.

#### **2. Vitamin D synthesis**

#### **2.1 The synthesis of vitamin D3 from the skin and the factors affecting this synthesis**

Formation of vitamin D3, which is the first step of vitamin D synthesis, takes place in the epidermis by a non-enzymatic process (**Figure 1**). Vitamin D3 is the most important source of vitamin D in the body. 90–95% of vitamin D3 in the human body is produced from the skin with the effect of sunlight. Therefore, sunlight is the main source of vitamin D synthesis, and if there is sufficient exposure to sunlight, there is no need to take additional vitamin D. The mechanism of non-enzymatic photolysis of vitamin D by ultraviolet B (UVB) rays with wavelengths in the range of 290–315 nm involves the breaking of a bond in the B ring of 7-dehydrocholesterol (pro-vitamin D3), resulting in pre-vitamin D3 formation in the epidermis. Subsequently, two different double bonds are formed between the broken carbon atoms in the B ring by thermo-sensitive non-enzymatic process, and the formation of vitamin D3 from pre-vitamin D3 is completed (**Figure 2**) [7].

The synthesis of vitamin D3 from pro-vitamin D3 in the skin is adjusted according to the needs of the organism. In a period of just fifteen minutes, previtamin D3 is synthesized from pro-vitamin D3 with the effect of ultraviolet light. Conversion from pre-vitamin D3 to vitamin D3 occurs by isomerization in a rather slow and thermo-sensitive manner. In the case of exposure to UV rays or solar radiation for a long period, pre-vitamin D3 converts to a number of photolyzed inactive by-products, such as lumisterol (irreversible) or tachysterol (which can be converted back to pre-vitamin D3). These by-products have no biological effects (**Figure 2**). In other words, once pre-vitamin D3 is formed in the skin, it turns into either vitamin D3 or inactive metabolites. This is a physiological control mechanism that protects the body from vitamin D intoxication by preventing unnecessary vitamin D synthesis [8, 9].

Some conditions that prevent UVB rays from reaching the skin cause a decrease in vitamin D production. One of these reasons is the ozone (O3) layer surrounding the atmosphere, which reflects some of the sun's rays, preventing them from reaching the Earth and their harmful carcinogenic effects on the skin.

**5**

*Vitamin D Metabolism*

**Figure 2.**

*DOI: http://dx.doi.org/10.5772/intechopen.97180*

*Vitamin D3 synthesis from 7-dehydrocholesterol in the epidermis.*

1000 units of oral vitamin D intake [2, 3, 8].

The peak UVB wavelength required for optimal vitamin D synthesis from the skin is 297 (290–315) nm [1, 8]. In addition, air pollution, aerosols, water vapors, and increased nitrogens in the air also play a role in preventing sunlight reaching the Earth, and consequently result in a potential reduced synthesis of vitamin D [8]. Another factor affecting the effectiveness of UVB rays in the synthesis of vitamin D in the skin is the solar zenith angle, which affects how UVB rays reach the world quantifiably. When the sun moves in a path closer to the horizon, which occurs in the northern latitudes in the winter season, vitamin D synthesis is more adversely affected (or reduced). In the summer time in the northern latitudes, a normal biosynthesis is more propitious or favorable. The narrowing of this angle indicates that the sun rays reach the Earth more steeply and intensely. The solar zenith angle is closely related to sunbathing time during the day, the seasons and the geographic region (latitude). Sunlight reaches the Earth most intensely in the "mid-day" when it is summer in the northern latitudes and the weather is clear. Finally, it is thought that sunlight exposure is sufficient for vitamin D synthesis in all geographic regions below 35 degrees north or south latitude all year round. In regions beyond this latitude toward the poles, especially in winter, sunlight is not sufficient for vitamin D synthesis. For example, UVB rays are not sufficient for vitamin D synthesis between October and April in Rome, which is located on 41.9 degrees north latitude, and between November and February in Berlin and Amsterdam, which are located on 52 degrees north latitude. For the reasons mentioned above, it is difficult to predict how much UVB rays reach the skin and how much of this increases serum vitamin D levels. In experimental studies, it has been reported that UVB rays that will cause minimal erythema in 25% of the skin are equivalent to

UVB rays are also affected by the individual's clothing style, use of sunscreen, and skin colour determined by pigmentation with melanin. In dressing style, especially the type of the clothing fabric used is of great importance [10]. Nonsynthetic, light-colored, and linen garments play a less preventive role in UV rays reaching the skin than do garments made of silk, nylon, polyester, and wools. For example, black-dyed cotton clothing prevents 98.6% of UVB rays from reaching the skin compared to white (undyed) cotton clothing, which blocks 47.7% of UVB. Topical sunscreens also prevent UVB rays from reaching the skin by absorbing, reflecting or dispersing them. Topical creams with a sun protection factor of 8 or higher block vitamin D synthesis above 95% [11]. Melanin is a large, opaque polymer synthesized by melanocytes in the skin through the stimulus of exposure to UVB rays. Melanin competes with dehydrocholesterol 7 in the skin to absorb UVB photons and thus inhibits vitamin D synthesis [12]. Individuals with dark skin

**Figure 1.** *Vitamin D metabolism.*

*Vitamin D*

enzymatic steps.

**synthesis**

**2. Vitamin D synthesis**

sary vitamin D synthesis [8, 9].

same way and are commonly referred to as vitamin D. Vitamin D is a prohormone and inactive, and to be activated, it must go through a series of enzymatic and non-

**2.1 The synthesis of vitamin D3 from the skin and the factors affecting this** 

Some conditions that prevent UVB rays from reaching the skin cause a decrease in vitamin D production. One of these reasons is the ozone (O3) layer surrounding the atmosphere, which reflects some of the sun's rays, preventing them from reaching the Earth and their harmful carcinogenic effects on the skin.

Formation of vitamin D3, which is the first step of vitamin D synthesis, takes place in the epidermis by a non-enzymatic process (**Figure 1**). Vitamin D3 is the most important source of vitamin D in the body. 90–95% of vitamin D3 in the human body is produced from the skin with the effect of sunlight. Therefore, sunlight is the main source of vitamin D synthesis, and if there is sufficient exposure to sunlight, there is no need to take additional vitamin D. The mechanism of non-enzymatic photolysis of vitamin D by ultraviolet B (UVB) rays with wavelengths in the range of 290–315 nm involves the breaking of a bond in the B ring of 7-dehydrocholesterol (pro-vitamin D3), resulting in pre-vitamin D3 formation in the epidermis. Subsequently, two different double bonds are formed between the broken carbon atoms in the B ring by thermo-sensitive non-enzymatic process, and the formation of vitamin D3 from pre-vitamin D3 is completed (**Figure 2**) [7]. The synthesis of vitamin D3 from pro-vitamin D3 in the skin is adjusted according to the needs of the organism. In a period of just fifteen minutes, previtamin D3 is synthesized from pro-vitamin D3 with the effect of ultraviolet light. Conversion from pre-vitamin D3 to vitamin D3 occurs by isomerization in a rather slow and thermo-sensitive manner. In the case of exposure to UV rays or solar radiation for a long period, pre-vitamin D3 converts to a number of photolyzed inactive by-products, such as lumisterol (irreversible) or tachysterol (which can be converted back to pre-vitamin D3). These by-products have no biological effects (**Figure 2**). In other words, once pre-vitamin D3 is formed in the skin, it turns into either vitamin D3 or inactive metabolites. This is a physiological control mechanism that protects the body from vitamin D intoxication by preventing unneces-

**4**

**Figure 1.**

*Vitamin D metabolism.*

**Figure 2.** *Vitamin D3 synthesis from 7-dehydrocholesterol in the epidermis.*

The peak UVB wavelength required for optimal vitamin D synthesis from the skin is 297 (290–315) nm [1, 8]. In addition, air pollution, aerosols, water vapors, and increased nitrogens in the air also play a role in preventing sunlight reaching the Earth, and consequently result in a potential reduced synthesis of vitamin D [8]. Another factor affecting the effectiveness of UVB rays in the synthesis of vitamin D in the skin is the solar zenith angle, which affects how UVB rays reach the world quantifiably. When the sun moves in a path closer to the horizon, which occurs in the northern latitudes in the winter season, vitamin D synthesis is more adversely affected (or reduced). In the summer time in the northern latitudes, a normal biosynthesis is more propitious or favorable. The narrowing of this angle indicates that the sun rays reach the Earth more steeply and intensely. The solar zenith angle is closely related to sunbathing time during the day, the seasons and the geographic region (latitude). Sunlight reaches the Earth most intensely in the "mid-day" when it is summer in the northern latitudes and the weather is clear. Finally, it is thought that sunlight exposure is sufficient for vitamin D synthesis in all geographic regions below 35 degrees north or south latitude all year round. In regions beyond this latitude toward the poles, especially in winter, sunlight is not sufficient for vitamin D synthesis. For example, UVB rays are not sufficient for vitamin D synthesis between October and April in Rome, which is located on 41.9 degrees north latitude, and between November and February in Berlin and Amsterdam, which are located on 52 degrees north latitude. For the reasons mentioned above, it is difficult to predict how much UVB rays reach the skin and how much of this increases serum vitamin D levels. In experimental studies, it has been reported that UVB rays that will cause minimal erythema in 25% of the skin are equivalent to 1000 units of oral vitamin D intake [2, 3, 8].

UVB rays are also affected by the individual's clothing style, use of sunscreen, and skin colour determined by pigmentation with melanin. In dressing style, especially the type of the clothing fabric used is of great importance [10]. Nonsynthetic, light-colored, and linen garments play a less preventive role in UV rays reaching the skin than do garments made of silk, nylon, polyester, and wools. For example, black-dyed cotton clothing prevents 98.6% of UVB rays from reaching the skin compared to white (undyed) cotton clothing, which blocks 47.7% of UVB. Topical sunscreens also prevent UVB rays from reaching the skin by absorbing, reflecting or dispersing them. Topical creams with a sun protection factor of 8 or higher block vitamin D synthesis above 95% [11]. Melanin is a large, opaque polymer synthesized by melanocytes in the skin through the stimulus of exposure to UVB rays. Melanin competes with dehydrocholesterol 7 in the skin to absorb UVB photons and thus inhibits vitamin D synthesis [12]. Individuals with dark skin colour have more melanin pigment in their epidermis than light-skinned individuals and require higher concentrations of sunlight for the same amount of vitamin D synthesis [12]. In addition, the 7-dehydrocholesterol level (provitamin D) in the epidermis can also affect the serum vitamin D concentration. For example, 7-dehydrocholesterol levels in scar tissue caused by the burn are reduced by 42.5% of normal. In these cases, progressive vitamin D deficiency develops, especially if supplemental dietary vitamin D is not provided. Moreover, the content of provitamin D in the skin decreases with age. Skin temperature is also important for vitamin D synthesis. Vitamin D from pre-vitamin D by isomerization whose rate of formation is temperature- dependent. The rate decreases as the skin temperature decreases. In a healthy person, the skin temperature is lower than the central body temperature and varies between 29 and 35 degrees Celcius. When the skin temperature is 37 degrees Celcius, the isomerization of vitamin D from pre-vitamin D occurs within 2.5 hours [13, 14].

#### *2.1.1 Biosynthesis of 25OHD3 (25-hydroxylase) in liver*

Vitamin D3 synthesized in the skin is released into the systemic circulation and all forms are transported by binding to VDBP in serum. A portion of vitamin D, a fat-soluble vitamin, is stored in adipose tissue for use when necessary. The ability of vitamin D to be stored in adipose tissue extends its total half-life in the body up to approximately 2 months. When vitamin D3 is transported to the liver, it is first converted into 25OHD3 by the cytochrome P450 25-hydroxylase enzyme. 25OHD3 is the main circulating form of vitamin D, and it is the parameter that provides the best estimation about the body's vitamin D pool [15]. Various enzymes that show 25-hydroxylase properties have been described in the body. Among these, the first one is CYP27A1 located in mitochondria, and the second is microsomally located CYP2R1 [1, 6, 16]. CYP27A1 also exerts 27-hydroxylase effect and is involved in bile acid synthesis. Although CYP27A1 is expressed in different tissues of the body, the tissues where it is most commonly found are liver and skeletal muscle tissues [1, 2]. In experimental studies, it was reported that the serum 25OHD3 levels were increased in mice which possess an inactivated CYP27A1 gene, and that rickets did not occur in these mice [17]. Interestingly, in this study, it was shown that CYP2R1 expression increased after CYP27A1 gene inactivation, and consequently 25-hydroxylation activity increased [17]. In addition, individuals with a CYP27A1 inactivating mutation develop a cerebrotendinous xanthomatosis disease with bile and cholesterol synthesis disorders, but without rickets manifestation [18]. Besides CYP27A1, different CYP-450 enzymes with 25-hydroxylase activity (CYP2D25, CYP2J2, CYP2J3, and CYP2C11) have been identified in humans and animals, with the most important one in human being CYP2R1. It is assumed that enzymes other than CYP2R1 have effects only on serum 25OHD3 levels [2].

Studies have suggested that CYP2R1 is the major enzyme responsible for 25-hydroxylation in the human body. This enzyme is expressed in many tissues, mainly liver, skin, and testis [1, 2, 17]. The 25-hydroxylase encoded by the CYP2R1 gene was first described by Cheng et al. [19]. It was first reported by Chen et al. [20] that homozygous inactivating mutations of this gene lead to clinically observed rickets (vitamin D-dependent rickets type IB) in Nigerian families. It has been reported that these cases gave suboptimal response to standard vitamin D (inactive vitamin D2 or D3 forms) treatment [21]. The CYP2R1 enzyme has equal affinity for the different forms of vitamin D precursors (D2 or D3) [19]. Studies have shown that 25-hydroxylase effect increased in male rats given estrogen, whereas this activity decreased in female rats given testosterone [21]. Despite experimental studies, the effect of sex steroids on 25-hydroxylase enzyme activity in humans is unknown.

**7**

*Vitamin D Metabolism*

*DOI: http://dx.doi.org/10.5772/intechopen.97180*

*(CYP27B1) in the kidney*

It has been shown that in CYP2R1-null mice, the level of 25OHD3 decreases by 50%, when both CYP2R1 and CYP27A1 are inactivated, and that serum 25OHD3 levels decrease by 70%, and serum 25OHD3 level remains at a measurable level in both cases [2, 17]. This supports the view that serum vitamin D level is compensated by

The final step of active vitamin D formation takes place in the proximal tubules of the kidney, led by the enzyme 1-alpha hydroxylase. 25OHD3, which is bound to VDBP, is taken into tubule cells and metabolized (1-alpha hydroxylation) through megalin and cubilin, which are transmembrane proteins located in renal tubules and act as surface receptors for VDBP in tubules. 25OHD3, which then undergoes 1-alpha hydroxylation [1, 2]. The 1-alpha hydroxylase enzyme hydroxylates the first carbon atom in the A ring of 25OHD3, resulting in the formation of 1,25 (OH) 2D3 [1]. CYP27B1 is the only enzyme that has 1-alpha hydroxylase activity. This enzyme, which belongs to the cytochrome P-450 enzyme system, is located in the inner mitochondrial membrane and carries out electron transport to NADPH via ferrodoxin-ferrodoxin reductase [1, 2]. The gene for the enzyme consists of nine exons and is located 12q14.1 chromosomal region. Four different groups reported the cloning and sequencing of the gene from rats, mice and humans [22–26]. In biallelic inactivating mutations of this enzyme, which is highly homologous to some mitochondria located cytochrome P-450 enzymes (CYP27A1 and CYP24A1), 25OHD3 cannot be converted to 1.25 (OH) 2D3, which is the active vitamin D form. In this case, the clinical picture of vitamin D-dependent rickets type 1A (also called pseudo-vitamin D deficiency rickets) occurs [23]. This disease is typically characterized by rickets, with clinically observed very low 1.25 (OH) 2D3, low serum calcium/phosphorus, and high parathyroid hormone (PTH) levels. CYP27B1

other enzymes with recruitable 25-hydroxylase enzyme activity.

*2.1.2 Formation of active vitamin D [1,25 (OH) 2D3] by 1-alpha hydroxylase* 

is expressed mainly in the renal proximal tubules and in the placenta during pregnancy [27]. While the expression of the gene encoding this enzyme increases with the effect of PTH, it decreases with FGF23 (fibroblast growth factor 23) and 1.25 (OH) 2D3. CYP27B1 gene is also expressed in lung, brain, breast and intestinal system epithelial cells, immune system cells (macrophage, T/B lymphocytes and dendritic cells), osteoblasts, chondrocytes, and some tumor cell types [1, 2]. The regulation of the extra-renal localized 1-alpha hydroxylase enzyme differs. In some granulomatous diseases where monocyte/macrophage cells play an important role (sarcoidosis, tuberculosis, Chron's disease, etc.), with the effect of IL-1, TNF-α, IFN-γ, 1-alpha hydroxylase enzyme activity increases and 1,25 (OH) 2D3 is synthesized in greater quantities than normal, and consequently, hypercalcemia and hypercalciuria emerge [28–30]. Additionally, since cells in these tissues do not have PTH receptors, it is not yet understood how PTH exerts its enhancing effect on the 1-alpha hydroxylase enzyme activity in these cells. In one study, it has been suggested that this enhancing effect of PTH may have occurred through posttranscriptional effects [31]. Moreover, 1-alpha hydroxylase enzyme in these cells is

not inhibited by 1,25 (OH) 2D3 or hypercalcemia, unlike the renal tubules.

The 24-hydroxylase enzyme is located in the mitochondrial inner membrane of the cells located in the proximal kidney and, like CYP27B1, uses the electron transport system that enables electron transport to NADPH via ferrodoxineferrodoxin reductase. It is known that CYP24A1, which is the only enzyme showing

*2.1.3 Inactivation of vitamin D by 24-hydroxylase (CYP24A1)*

#### *Vitamin D Metabolism DOI: http://dx.doi.org/10.5772/intechopen.97180*

*Vitamin D*

occurs within 2.5 hours [13, 14].

*2.1.1 Biosynthesis of 25OHD3 (25-hydroxylase) in liver*

than CYP2R1 have effects only on serum 25OHD3 levels [2].

Studies have suggested that CYP2R1 is the major enzyme responsible for 25-hydroxylation in the human body. This enzyme is expressed in many tissues, mainly liver, skin, and testis [1, 2, 17]. The 25-hydroxylase encoded by the CYP2R1 gene was first described by Cheng et al. [19]. It was first reported by Chen et al. [20] that homozygous inactivating mutations of this gene lead to clinically observed rickets (vitamin D-dependent rickets type IB) in Nigerian families. It has been reported that these cases gave suboptimal response to standard vitamin D (inactive vitamin D2 or D3 forms) treatment [21]. The CYP2R1 enzyme has equal affinity for the different forms of vitamin D precursors (D2 or D3) [19]. Studies have shown that 25-hydroxylase effect increased in male rats given estrogen, whereas this activity decreased in female rats given testosterone [21]. Despite experimental studies, the effect of sex steroids on 25-hydroxylase enzyme activity in humans is unknown.

colour have more melanin pigment in their epidermis than light-skinned individuals and require higher concentrations of sunlight for the same amount of vitamin D synthesis [12]. In addition, the 7-dehydrocholesterol level (provitamin D) in the epidermis can also affect the serum vitamin D concentration. For example, 7-dehydrocholesterol levels in scar tissue caused by the burn are reduced by 42.5% of normal. In these cases, progressive vitamin D deficiency develops, especially if supplemental dietary vitamin D is not provided. Moreover, the content of provitamin D in the skin decreases with age. Skin temperature is also important for vitamin D synthesis. Vitamin D from pre-vitamin D by isomerization whose rate of formation is temperature- dependent. The rate decreases as the skin temperature decreases. In a healthy person, the skin temperature is lower than the central body temperature and varies between 29 and 35 degrees Celcius. When the skin temperature is 37 degrees Celcius, the isomerization of vitamin D from pre-vitamin D

Vitamin D3 synthesized in the skin is released into the systemic circulation and all forms are transported by binding to VDBP in serum. A portion of vitamin D, a fat-soluble vitamin, is stored in adipose tissue for use when necessary. The ability of vitamin D to be stored in adipose tissue extends its total half-life in the body up to approximately 2 months. When vitamin D3 is transported to the liver, it is first converted into 25OHD3 by the cytochrome P450 25-hydroxylase enzyme. 25OHD3 is the main circulating form of vitamin D, and it is the parameter that provides the best estimation about the body's vitamin D pool [15]. Various enzymes that show 25-hydroxylase properties have been described in the body. Among these, the first one is CYP27A1 located in mitochondria, and the second is microsomally located CYP2R1 [1, 6, 16]. CYP27A1 also exerts 27-hydroxylase effect and is involved in bile acid synthesis. Although CYP27A1 is expressed in different tissues of the body, the tissues where it is most commonly found are liver and skeletal muscle tissues [1, 2]. In experimental studies, it was reported that the serum 25OHD3 levels were increased in mice which possess an inactivated CYP27A1 gene, and that rickets did not occur in these mice [17]. Interestingly, in this study, it was shown that CYP2R1 expression increased after CYP27A1 gene inactivation, and consequently 25-hydroxylation activity increased [17]. In addition, individuals with a CYP27A1 inactivating mutation develop a cerebrotendinous xanthomatosis disease with bile and cholesterol synthesis disorders, but without rickets manifestation [18]. Besides CYP27A1, different CYP-450 enzymes with 25-hydroxylase activity (CYP2D25, CYP2J2, CYP2J3, and CYP2C11) have been identified in humans and animals, with the most important one in human being CYP2R1. It is assumed that enzymes other

**6**

It has been shown that in CYP2R1-null mice, the level of 25OHD3 decreases by 50%, when both CYP2R1 and CYP27A1 are inactivated, and that serum 25OHD3 levels decrease by 70%, and serum 25OHD3 level remains at a measurable level in both cases [2, 17]. This supports the view that serum vitamin D level is compensated by other enzymes with recruitable 25-hydroxylase enzyme activity.

#### *2.1.2 Formation of active vitamin D [1,25 (OH) 2D3] by 1-alpha hydroxylase (CYP27B1) in the kidney*

The final step of active vitamin D formation takes place in the proximal tubules of the kidney, led by the enzyme 1-alpha hydroxylase. 25OHD3, which is bound to VDBP, is taken into tubule cells and metabolized (1-alpha hydroxylation) through megalin and cubilin, which are transmembrane proteins located in renal tubules and act as surface receptors for VDBP in tubules. 25OHD3, which then undergoes 1-alpha hydroxylation [1, 2]. The 1-alpha hydroxylase enzyme hydroxylates the first carbon atom in the A ring of 25OHD3, resulting in the formation of 1,25 (OH) 2D3 [1]. CYP27B1 is the only enzyme that has 1-alpha hydroxylase activity. This enzyme, which belongs to the cytochrome P-450 enzyme system, is located in the inner mitochondrial membrane and carries out electron transport to NADPH via ferrodoxin-ferrodoxin reductase [1, 2]. The gene for the enzyme consists of nine exons and is located 12q14.1 chromosomal region. Four different groups reported the cloning and sequencing of the gene from rats, mice and humans [22–26]. In biallelic inactivating mutations of this enzyme, which is highly homologous to some mitochondria located cytochrome P-450 enzymes (CYP27A1 and CYP24A1), 25OHD3 cannot be converted to 1.25 (OH) 2D3, which is the active vitamin D form. In this case, the clinical picture of vitamin D-dependent rickets type 1A (also called pseudo-vitamin D deficiency rickets) occurs [23]. This disease is typically characterized by rickets, with clinically observed very low 1.25 (OH) 2D3, low serum calcium/phosphorus, and high parathyroid hormone (PTH) levels. CYP27B1 is expressed mainly in the renal proximal tubules and in the placenta during pregnancy [27]. While the expression of the gene encoding this enzyme increases with the effect of PTH, it decreases with FGF23 (fibroblast growth factor 23) and 1.25 (OH) 2D3. CYP27B1 gene is also expressed in lung, brain, breast and intestinal system epithelial cells, immune system cells (macrophage, T/B lymphocytes and dendritic cells), osteoblasts, chondrocytes, and some tumor cell types [1, 2]. The regulation of the extra-renal localized 1-alpha hydroxylase enzyme differs. In some granulomatous diseases where monocyte/macrophage cells play an important role (sarcoidosis, tuberculosis, Chron's disease, etc.), with the effect of IL-1, TNF-α, IFN-γ, 1-alpha hydroxylase enzyme activity increases and 1,25 (OH) 2D3 is synthesized in greater quantities than normal, and consequently, hypercalcemia and hypercalciuria emerge [28–30]. Additionally, since cells in these tissues do not have PTH receptors, it is not yet understood how PTH exerts its enhancing effect on the 1-alpha hydroxylase enzyme activity in these cells. In one study, it has been suggested that this enhancing effect of PTH may have occurred through posttranscriptional effects [31]. Moreover, 1-alpha hydroxylase enzyme in these cells is not inhibited by 1,25 (OH) 2D3 or hypercalcemia, unlike the renal tubules.

#### *2.1.3 Inactivation of vitamin D by 24-hydroxylase (CYP24A1)*

The 24-hydroxylase enzyme is located in the mitochondrial inner membrane of the cells located in the proximal kidney and, like CYP27B1, uses the electron transport system that enables electron transport to NADPH via ferrodoxineferrodoxin reductase. It is known that CYP24A1, which is the only enzyme showing 24-hydroxylase enzyme activity in humans, can also exhibit 23-hydroxylase enzyme activity [2]. Which enzyme will be more prominent varies according to the species [32]. The 23-hydroxylase, another enzyme that degrades vitamin D, is the first step activity in the conversion of 1,25 (OH) 2D3 to 1,25 (OH) 2D3-23,26-lactone.

The CYP24A1 enzyme, encoded in 20q13 chromosomal region and having 24-hydroxylase enzyme activity, initiates catabolic processes that lead to the inactivation of vitamin D by hydroxylating the 24th carbon atom. This enzyme can use both 25OHD3 and 1.25 (OH) 2D3 as substrates, but has a higher affinity for 1.25 (OH) 2D3. As a result of a series of enzymatic reactions, calcitroic acid is formed, which becomes biologically inactive. On the other hand, it has been suggested that the 1,25 (OH) 2D3-23,26-lactone, which is formed in the 23-hydroxylase pathway, lowers serum calcium level, inhibits bone resorption induced by 1.25 (OH) 2D3, and stimulates the formation of collagen tissue in bone tissue [33]. In addition, it has been suggested that 24,25 (OH) 2D3 is not only a degradation product, but has an important role in bone metabolism, especially in endochondral bone formation [34].

There are two vitamin D response elements (VDRE) in the promoter region of the CYP24A1 gene [35]. When active vitamin D is bound to the these one of VDRE after heterodimerization with various molecules, thus initiates the inactivation process of vitamin D. In addition, it has been shown that CYP24A1 gene expression decreases with the effect of PTH, whereas it increases with increased FGF23 concentrations [1, 32, 36, 37]. Inactivating mutations in CYP24A1 lead to an idiopathic infantile hypercalcemia clinic characterized by hypercalcemia, hypercalciuria, nephrocalcinosis, low PTH, low 24.25 (OH) 2D3 and high 1.25 (OH) 2D3 levels [37]. As a result, CYP24A1 is a critical enzyme that protects the body from excessive accumulation and possible intoxication of vitamin D.

#### *2.1.4 3-epimerization of Vitamin D*

3-epimerase activity was first demonstrated in 2001, with the detection of the 3-epi form of 1,25 (OH) 2D3 in keratinocytes [38]. In the following years, epimer forms of 25OHD3 and other vitamin D metabolites were discovered. However, the enzyme or enzymes involved in epimerization has not yet been identifiedpurified or cloned. This enzyme changes the hydroxyl group in the 3rd carbon of the A ring from the alpha orientation to the beta orientation, causing the three-dimensional structure to change and consequently alter the activity of CYP27B1 and CYP24A1 enzymes on vitamin D metabolism. These epimers can be detected by special liquid chromatography-mass spectroscopy (LC-MC) measurement methods [2]. C-3 epimer forms of 25OHD3 and 1,25 (OH) 2D3 have been shown to have lower affinity for VDR and VDBP compared to non-epimer forms [38]. The C-3 epimer form of 1,25 (OH) 2D3 has been shown to cause PTH suppression similar to the non-epimer form, but its effects on bone tissue are not clear. In addition, epimer forms have also been shown to have non-calcium effects (anti-proliferative effect, surfactant synthesis) [39]. It has been shown that the serum levels of vitamin C-3 epimer forms are found to be 60% higher in the period between the neonatal period and one year old, and decrease after one year of age and decrease to very low levels in adulthood [2, 38]. The reason why epimer forms with limited biological activity are important is that they cause interference and false high results in serum 25OHD3 and 25OHD2 measurement. Therefore, it is important to prefer the method (especially LC–MS / MS) that can exclude this effect of epimer forms that cause serum vitamin D measurement interference. However, the use of LC–MS/MS method in the measurement of vitamin D has not become widespread in the world, and the use of this method is only recommended in selected cases.

**9**

stress [1–3, 47].

**3.1 Genomic effect of Vitamin D**

*Vitamin D Metabolism*

*2.1.5 Transport of Vitamin D*

*DOI: http://dx.doi.org/10.5772/intechopen.97180*

the affinity of VDBP on vitamin D metabolites [1, 45, 46].

Vitamin D provides its biological effect in two different ways. The first is by directly affecting gene transcription (genomic effect) as other steroid hormones. This effect is relatively slow and usually occurs within hours or days. The second is the non-genomic pathway whose biological effect is relatively faster (within minutes). Vitamin D exerts its non-genomic effect by directly altering the transmembrane passage of some ions (Ca, Cl) or by affecting intracellular signaling pathway activities (cAMP, PKA, PLC, PI-3 kinase and MAP kinase) [1, 2]. Genetic studies on vitamin D support that active vitamin D directly or indirectly regulates 0.8–5% of the total genome, suggesting the role of active vitamin D in many actions such as regulation of cellular growth, DNA repair, differentiation, apoptosis, membrane transport, cellular metabolism, adhesion and oxidative

The active form of vitamin D displays this effect through the vitamin D receptor (VDR). VDR is a member of the nuclear hormone receptor superfamily, which includes steroid, thyroid hormone, and retinoic acid receptors [48]. The VDR gene located on chromosome 12 consists of 427 amino acids encoded by. The structure of the VDR consists of a relatively short N-terminal domain compared to other nuclear receptors, two zinc-fingers that allow the receptor to bind to DNA, and a highly

**3. The mechanism of Vitamin D actions**

The largest part of the circulating vitamin D is in the form of 25OHD3, and its serum concentration is in equilibrium with the level of vitamin D stored in muscle and adipose tissues. The parameter that gives the best information about the whole vitamin D pool in the body is 25OHD3 and its known half-life of 15–20 days. Most of all forms of vitamin D in circulation (85–88%) are transported by binding to VDBP and the remaining part (12–15%) to albumin [2, 40]. The serum concentration of VDBP is 4–8 nM and only 2% of it is bound with vitamin D metabolites [2]. Moreover, the affinity of VDBP to 25OHD3 is 20 times higher than 1.25 (OH) 2D3 [3]. 0.03% of 25OHD3 and 0.4% of 1.25 (OH) 2D3 are in free form [2]. In chronic liver disease or nephrotic syndrome, VDBP and albumin levels and thus total serum 25OHD3 and 1.25 (OH) 2D3 levels decrease, but the levels of free forms are not affected [41]. Likewise, since the VDBP level may decrease during the acute disease period, evaluating the body's vitamin D pool by measuring the serum 25OHD3 level with standard immunoassays may lead to misinterpretations [42]. In conclusion, while the total levels of vitamin D forms are affected by the VDBP level, there is no relationship between VDBP and free vitamin D forms, which are essential for biological activity. It was shown that both 25OHD3 and 1.25 (OH) 2D3 levels in VDBP-null mice were lower than wild type mice, but serum PTH and calcium levels were similarly normal in both groups [43]. This supports the view that serum vitamin D level measured by the standard method may not be an indicator of biologically active vitamin D pool. In addition, the predisposition of VDBP-null mice to the development of osteomalacia after a vitamin D-restricted diet suggests that VDBP may play a role in maintaining the existing vitamin D pool [44]. In addition, some single nucleotide polymorphisms (GC1F, GC1S, GC2) in the *VDBP* gene have been shown to impact

#### *2.1.5 Transport of Vitamin D*

*Vitamin D*

dral bone formation [34].

accumulation and possible intoxication of vitamin D.

of this method is only recommended in selected cases.

*2.1.4 3-epimerization of Vitamin D*

24-hydroxylase enzyme activity in humans, can also exhibit 23-hydroxylase enzyme activity [2]. Which enzyme will be more prominent varies according to the species [32]. The 23-hydroxylase, another enzyme that degrades vitamin D, is the first step

There are two vitamin D response elements (VDRE) in the promoter region of the CYP24A1 gene [35]. When active vitamin D is bound to the these one of VDRE after heterodimerization with various molecules, thus initiates the inactivation process of vitamin D. In addition, it has been shown that CYP24A1 gene expression decreases with the effect of PTH, whereas it increases with increased FGF23 concentrations [1, 32, 36, 37]. Inactivating mutations in CYP24A1 lead to an idiopathic infantile hypercalcemia clinic characterized by hypercalcemia, hypercalciuria, nephrocalcinosis, low PTH, low 24.25 (OH) 2D3 and high 1.25 (OH) 2D3 levels [37]. As a result, CYP24A1 is a critical enzyme that protects the body from excessive

3-epimerase activity was first demonstrated in 2001, with the detection of the 3-epi form of 1,25 (OH) 2D3 in keratinocytes [38]. In the following years, epimer forms of 25OHD3 and other vitamin D metabolites were discovered. However, the enzyme or enzymes involved in epimerization has not yet been identifiedpurified or cloned. This enzyme changes the hydroxyl group in the 3rd carbon of the A ring from the alpha orientation to the beta orientation, causing the three-dimensional structure to change and consequently alter the activity of CYP27B1 and CYP24A1 enzymes on vitamin D metabolism. These epimers can be detected by special liquid chromatography-mass spectroscopy (LC-MC) measurement methods [2]. C-3 epimer forms of 25OHD3 and 1,25 (OH) 2D3 have been shown to have lower affinity for VDR and VDBP compared to non-epimer forms [38]. The C-3 epimer form of 1,25 (OH) 2D3 has been shown to cause PTH suppression similar to the non-epimer form, but its effects on bone tissue are not clear. In addition, epimer forms have also been shown to have non-calcium effects (anti-proliferative effect, surfactant synthesis) [39]. It has been shown that the serum levels of vitamin C-3 epimer forms are found to be 60% higher in the period between the neonatal period and one year old, and decrease after one year of age and decrease to very low levels in adulthood [2, 38]. The reason why epimer forms with limited biological activity are important is that they cause interference and false high results in serum 25OHD3 and 25OHD2 measurement. Therefore, it is important to prefer the method (especially LC–MS / MS) that can exclude this effect of epimer forms that cause serum vitamin D measurement interference. However, the use of LC–MS/MS method in the measurement of vitamin D has not become widespread in the world, and the use

activity in the conversion of 1,25 (OH) 2D3 to 1,25 (OH) 2D3-23,26-lactone. The CYP24A1 enzyme, encoded in 20q13 chromosomal region and having 24-hydroxylase enzyme activity, initiates catabolic processes that lead to the inactivation of vitamin D by hydroxylating the 24th carbon atom. This enzyme can use both 25OHD3 and 1.25 (OH) 2D3 as substrates, but has a higher affinity for 1.25 (OH) 2D3. As a result of a series of enzymatic reactions, calcitroic acid is formed, which becomes biologically inactive. On the other hand, it has been suggested that the 1,25 (OH) 2D3-23,26-lactone, which is formed in the 23-hydroxylase pathway, lowers serum calcium level, inhibits bone resorption induced by 1.25 (OH) 2D3, and stimulates the formation of collagen tissue in bone tissue [33]. In addition, it has been suggested that 24,25 (OH) 2D3 is not only a degradation product, but has an important role in bone metabolism, especially in endochon-

**8**

The largest part of the circulating vitamin D is in the form of 25OHD3, and its serum concentration is in equilibrium with the level of vitamin D stored in muscle and adipose tissues. The parameter that gives the best information about the whole vitamin D pool in the body is 25OHD3 and its known half-life of 15–20 days. Most of all forms of vitamin D in circulation (85–88%) are transported by binding to VDBP and the remaining part (12–15%) to albumin [2, 40]. The serum concentration of VDBP is 4–8 nM and only 2% of it is bound with vitamin D metabolites [2]. Moreover, the affinity of VDBP to 25OHD3 is 20 times higher than 1.25 (OH) 2D3 [3]. 0.03% of 25OHD3 and 0.4% of 1.25 (OH) 2D3 are in free form [2]. In chronic liver disease or nephrotic syndrome, VDBP and albumin levels and thus total serum 25OHD3 and 1.25 (OH) 2D3 levels decrease, but the levels of free forms are not affected [41]. Likewise, since the VDBP level may decrease during the acute disease period, evaluating the body's vitamin D pool by measuring the serum 25OHD3 level with standard immunoassays may lead to misinterpretations [42]. In conclusion, while the total levels of vitamin D forms are affected by the VDBP level, there is no relationship between VDBP and free vitamin D forms, which are essential for biological activity. It was shown that both 25OHD3 and 1.25 (OH) 2D3 levels in VDBP-null mice were lower than wild type mice, but serum PTH and calcium levels were similarly normal in both groups [43]. This supports the view that serum vitamin D level measured by the standard method may not be an indicator of biologically active vitamin D pool. In addition, the predisposition of VDBP-null mice to the development of osteomalacia after a vitamin D-restricted diet suggests that VDBP may play a role in maintaining the existing vitamin D pool [44]. In addition, some single nucleotide polymorphisms (GC1F, GC1S, GC2) in the *VDBP* gene have been shown to impact the affinity of VDBP on vitamin D metabolites [1, 45, 46].

#### **3. The mechanism of Vitamin D actions**

Vitamin D provides its biological effect in two different ways. The first is by directly affecting gene transcription (genomic effect) as other steroid hormones. This effect is relatively slow and usually occurs within hours or days. The second is the non-genomic pathway whose biological effect is relatively faster (within minutes). Vitamin D exerts its non-genomic effect by directly altering the transmembrane passage of some ions (Ca, Cl) or by affecting intracellular signaling pathway activities (cAMP, PKA, PLC, PI-3 kinase and MAP kinase) [1, 2]. Genetic studies on vitamin D support that active vitamin D directly or indirectly regulates 0.8–5% of the total genome, suggesting the role of active vitamin D in many actions such as regulation of cellular growth, DNA repair, differentiation, apoptosis, membrane transport, cellular metabolism, adhesion and oxidative stress [1–3, 47].

#### **3.1 Genomic effect of Vitamin D**

The active form of vitamin D displays this effect through the vitamin D receptor (VDR). VDR is a member of the nuclear hormone receptor superfamily, which includes steroid, thyroid hormone, and retinoic acid receptors [48]. The VDR gene located on chromosome 12 consists of 427 amino acids encoded by. The structure of the VDR consists of a relatively short N-terminal domain compared to other nuclear receptors, two zinc-fingers that allow the receptor to bind to DNA, and a highly

**Figure 3.** *The structure of the Vitamin D receptor (VDR).*

variable C-terminal region, and the hinge region connecting binding these domains (**Figure 3**) [2]. The DNA-binding region of the receptor is rich in cysteine, and the sequence of this region is largely conserved between species. The zinc-finger structure close to the C-terminal part of VDR determines the specificity for the VDRE (vitamin D response element), which is the binding site on the DNA. The other zinc-finger structure is involved in the heterodimerization of VDR with RXR (retinoid X receptor) [1, 2]. The ligand-binding part of the receptor consists of 12 α-helix structures (H1-12; the H12 part is also called AF2) and 3 β-sheet structures (S1-3) [49]. The AF-2 region located at the end of the C-terminal is the binding site of co-activator complex structures such as SRC (steroid receptor coactivator) and DRIP (vitamin D receptor interacting protein). Transcription is initiated by binding co-activators to this region [50]. Apart from these functional domains, there are NLS (nuclear localization signal) regions within the DNA binding region of VDR, which are necessary for maintaining transcriptional activity [2]. In addition, there is a hinge region between the ligand-binding and DNA-binding domains of the VDR that ensures molecule stabilization.

After active vitamin D crosses the target cell membrane, it interacts with the ligand-binding domain of its own receptor (VDR) in the cytoplasm of the cell. Vitamin D is embedded in the ligand-binding domain, and subsequently, in the H12 alpha-helix H12 (AF-2) region, which is located at the end of the ligand binding part [51]. This critical conformational change of AF-2 facilitates the binding of co-activators in later stages [52]. In the next step, vitamin D-bound VDR binds to RXRα to form a VDR/RXR heterodimer structure that binds to cognate VDR elements (VDRE) in the promoter region in the target genes with a high affinity to initiate gene activation or inhibition. There are many genespecific VDREs associated with bone metabolism, xenobiotic detoxification, drug resistance, cell growth and differentiation, angiogenesis, mammalian hair growth cycle, lipid synthesis regulation, apoptosis, and immune functions, suggesting that vitamin D has numerous regulatory roles in various organs or tissues in the body [53].

After active vitamin D-VDR-RXR-VDRE interaction, the progression of transcription is controlled by co-activator and co-repressors. The best known co-activators are the p160 co-activator family (eg CBP/p300 and p/CAF) and SRC 1,2,3. Both bind to the AF-2 part and have histone acetyl transferase (HAT) activity, which enables the opening of the histone structure and thus facilitates gene expression [54]. The SRC complex has three NR regions that facilitate binding and contain LxxLL (L, leucine; x, any amino acid) motifs. Likewise, the DRIP complex (Mediator) also has NR regions with LxxLL motifs consisting of 15 or more amino acids [55]. Unlike SRC, DRIP complex does not have HAT activity. This suggests the fact that both protein complexes play a complementary role in the initiation of transcription. The mediator multi-protein complex DRIP205/ MED1 (also known as MED1) accumulates around RNA polymerase 2of the initiation complex. This complex then interacts with the TATA region in the promoter

**11**

**Figure 4.**

*the membrane.*

*Vitamin D Metabolism*

*DOI: http://dx.doi.org/10.5772/intechopen.97180*

**3.2 Non-genomic effects of vitamin D**

unfolding of the histone core.

region and enables transcription to be initiated [56]. Co-repressors (eg SMRT and NCoR) have histone de-acetylase activity and inhibit transcription by preventing

Some of the hormones that act on the nuclear hormone receptor can also exert their biological effects on the membrane receptor without the need for additional gene regulation [2]. The non-genomic effect occurs through messenger-mediated pathways. Estrogen, progesterone, testosterone, corticosteroids and thyroid hormones have been reported to exert their effects by using both genomic and nongenomic pathways [2]. Vitamin D has been shown to directly regulate the activation or distribution of various ion-transport channel proteins (for calcium and chloride) and of enzymes (protein kinase C and phospholipase C) through the membrane receptor in osteoblast, liver, muscle, and intestinal cells (**Figure 4**) [57–62]. In order to demonstrate the non-genomic effect of vitamin D, many studies have been conducted on intestinal calcium absorption. Rapid vesicular calcium absorption (also called transcaltachia) has been shown in the chick intestinal tract [63]. Further experimental studies have shown that intestinal calcium transport cannot be blocked by the administration of actinomycin D (which inhibits the genomic effect) [64], whereas calcium absorption can be blocked by inhibition of voltage-

gated L-type calcium channel proteins [65] or by protein kinase C [66].

shown to be ineffective in calcium metabolism [67].

Apart from the intestinal system, it has been suggested that the non-genomic effect also occurs in chondrocytes in the growth plate and keratinocytes in the skin [67, 68]. Vitamin D is believed to exert its non-genomic effects through VDR analog and MARRS (also known as ERp57/GRp58/ERp60) receptors located on the cell membrane [69, 70]. These membrane receptors are located within the caveolar lipid layer [71]. In addition, research findings indicate that VDR is also necessary for the expression of membrane receptors that involve in the emergence of nongenomic effect [1, 2]. In studies evaluating the effects of vitamin D analogs (6-s-cis or 6-s-trans conformations), the 6-s-cis form can activate intestinal rapid calcium entry even though the VDR affinity is very low, whereas the 6-s-trans form has been

*Representation of the signal transduction pathways where Vitamin D has its non-genomic effect (2). After vitamin D binds to the membrane receptor, GDP in the G protein* α*-subunit turns into GTP and activation occurs. The* α*-subunit of the G protein is separated from other subunits and binds to phospholipase C (PLC). The PLC is then activated to convert phosphoinositol bisphosphate (PIP2) to inositol triphosphate (IP3) and diacylglycerol (DAG). Calcium release from the endoplasmic reticulum via the IP3 receptor (IP3R); DAG activates PKC. PKC, on the other hand, provides calcium entry into the cell via the L-type calcium channel in*  *Vitamin D*

**Figure 3.**

that ensures molecule stabilization.

*The structure of the Vitamin D receptor (VDR).*

variable C-terminal region, and the hinge region connecting binding these domains (**Figure 3**) [2]. The DNA-binding region of the receptor is rich in cysteine, and the sequence of this region is largely conserved between species. The zinc-finger structure close to the C-terminal part of VDR determines the specificity for the VDRE (vitamin D response element), which is the binding site on the DNA. The other zinc-finger structure is involved in the heterodimerization of VDR with RXR (retinoid X receptor) [1, 2]. The ligand-binding part of the receptor consists of 12 α-helix structures (H1-12; the H12 part is also called AF2) and 3 β-sheet structures (S1-3) [49]. The AF-2 region located at the end of the C-terminal is the binding site of co-activator complex structures such as SRC (steroid receptor coactivator) and DRIP (vitamin D receptor interacting protein). Transcription is initiated by binding co-activators to this region [50]. Apart from these functional domains, there are NLS (nuclear localization signal) regions within the DNA binding region of VDR, which are necessary for maintaining transcriptional activity [2]. In addition, there is a hinge region between the ligand-binding and DNA-binding domains of the VDR

After active vitamin D crosses the target cell membrane, it interacts with the ligand-binding domain of its own receptor (VDR) in the cytoplasm of the cell. Vitamin D is embedded in the ligand-binding domain, and subsequently, in the H12 alpha-helix H12 (AF-2) region, which is located at the end of the ligand binding part [51]. This critical conformational change of AF-2 facilitates the binding of co-activators in later stages [52]. In the next step, vitamin D-bound VDR binds to RXRα to form a VDR/RXR heterodimer structure that binds to cognate VDR elements (VDRE) in the promoter region in the target genes with a high affinity to initiate gene activation or inhibition. There are many genespecific VDREs associated with bone metabolism, xenobiotic detoxification, drug resistance, cell growth and differentiation, angiogenesis, mammalian hair growth cycle, lipid synthesis regulation, apoptosis, and immune functions, suggesting that vitamin D has numerous regulatory roles in various organs or tissues

After active vitamin D-VDR-RXR-VDRE interaction, the progression of transcription is controlled by co-activator and co-repressors. The best known co-activators are the p160 co-activator family (eg CBP/p300 and p/CAF) and SRC 1,2,3. Both bind to the AF-2 part and have histone acetyl transferase (HAT) activity, which enables the opening of the histone structure and thus facilitates gene expression [54]. The SRC complex has three NR regions that facilitate binding and contain LxxLL (L, leucine; x, any amino acid) motifs. Likewise, the DRIP complex (Mediator) also has NR regions with LxxLL motifs consisting of 15 or more amino acids [55]. Unlike SRC, DRIP complex does not have HAT activity. This suggests the fact that both protein complexes play a complementary role in the initiation of transcription. The mediator multi-protein complex DRIP205/ MED1 (also known as MED1) accumulates around RNA polymerase 2of the initiation complex. This complex then interacts with the TATA region in the promoter

**10**

in the body [53].

region and enables transcription to be initiated [56]. Co-repressors (eg SMRT and NCoR) have histone de-acetylase activity and inhibit transcription by preventing unfolding of the histone core.

#### **3.2 Non-genomic effects of vitamin D**

Some of the hormones that act on the nuclear hormone receptor can also exert their biological effects on the membrane receptor without the need for additional gene regulation [2]. The non-genomic effect occurs through messenger-mediated pathways. Estrogen, progesterone, testosterone, corticosteroids and thyroid hormones have been reported to exert their effects by using both genomic and nongenomic pathways [2]. Vitamin D has been shown to directly regulate the activation or distribution of various ion-transport channel proteins (for calcium and chloride) and of enzymes (protein kinase C and phospholipase C) through the membrane receptor in osteoblast, liver, muscle, and intestinal cells (**Figure 4**) [57–62]. In order to demonstrate the non-genomic effect of vitamin D, many studies have been conducted on intestinal calcium absorption. Rapid vesicular calcium absorption (also called transcaltachia) has been shown in the chick intestinal tract [63]. Further experimental studies have shown that intestinal calcium transport cannot be blocked by the administration of actinomycin D (which inhibits the genomic effect) [64], whereas calcium absorption can be blocked by inhibition of voltagegated L-type calcium channel proteins [65] or by protein kinase C [66].

Apart from the intestinal system, it has been suggested that the non-genomic effect also occurs in chondrocytes in the growth plate and keratinocytes in the skin [67, 68]. Vitamin D is believed to exert its non-genomic effects through VDR analog and MARRS (also known as ERp57/GRp58/ERp60) receptors located on the cell membrane [69, 70]. These membrane receptors are located within the caveolar lipid layer [71]. In addition, research findings indicate that VDR is also necessary for the expression of membrane receptors that involve in the emergence of nongenomic effect [1, 2]. In studies evaluating the effects of vitamin D analogs (6-s-cis or 6-s-trans conformations), the 6-s-cis form can activate intestinal rapid calcium entry even though the VDR affinity is very low, whereas the 6-s-trans form has been shown to be ineffective in calcium metabolism [67].

#### **Figure 4.**

*Representation of the signal transduction pathways where Vitamin D has its non-genomic effect (2). After vitamin D binds to the membrane receptor, GDP in the G protein* α*-subunit turns into GTP and activation occurs. The* α*-subunit of the G protein is separated from other subunits and binds to phospholipase C (PLC). The PLC is then activated to convert phosphoinositol bisphosphate (PIP2) to inositol triphosphate (IP3) and diacylglycerol (DAG). Calcium release from the endoplasmic reticulum via the IP3 receptor (IP3R); DAG activates PKC. PKC, on the other hand, provides calcium entry into the cell via the L-type calcium channel in the membrane.*

#### **4. Effects of Vitamin D on calcium and phosphorus**

#### **4.1 Intestinal calcium absorption**

One of the most important functions of vitamin D is to increase calcium absorption from the intestines. Calcium absorption from the intestinal tract occurs transcellular and para-cellular processes mediated through genomic and non-genomic effects. Among these, the trans-cellular pathway largely utilized by the intestinal system, which is regulated by vitamin D [2]. The absorption effect of vitamin D with non-genomic effect of calcium occurs directly on the membrane (transcaltachia). The channel-mediated calcium absorption effect of vitamin D occurs more slowly [2].

Calcium enters the epithelian cell by the effect of an electrical and chemical gradient via calcium channel protein TRPV6 (which has significant sequence homology to TRPV5 in the kidney), the transmembrane protein at the lumenal brush border edge of the intestinal epithelial cell. The expression of TRPV6 is activated by vitamin D [72]. Reduced intestinal calcium transport is observed in TRPV6 null mice [73]. Calcium entering the cell binds to calmodulin (CaM), which is bound with myosin 1A (also known as brush border myosin I). This formed complex allows calcium to be transported across the microvilli. Subsequently, the transport of calcium up to the basolateral membrane occurs inside the vesicle via calbindin-D9k (CaBP). The affinity of calcium for calbindinin is greater than for calmodulin, and better facilitates calcium transport inside the cell [74]. The calcium reaching the basolateral membrane is pumped out of the cell to systemic circulation via the Ca-ATPase (PMCA1b) pump located on the membrane [1, 2]. In addition, although it is less important, NCX (sodium/calcium exchanger), located in the basolateral region, also plays a role in excretion of calcium [2, 75]. Vitamin D shows its increasing effect on intestinal calcium absorption by inducing expression of TRPV6, CaBP and PMCAb and increasing the binding affinity of CaM to myosin 1A [1, 2].

Intestinal calcium absorption, serum calcium level and bone mineral content in Kalbindin D9k null mice (regardless of dietary calcium level) have been shown to be similar to normal mice [76]. Intestinal calcium absorption was found to be normal in calbindin D9k and TRPV6 null mice when a diet containing the daily requirement for calcium was given [77]. These findings indicate there is a mechanism other than the genomic effect through which vitamin D exerts its action (a non-genomic effect) in calcium absorption in the intestines when the amount of calcium in the diet is sufficient.

While trans-cellular calcium absorption is effective in compensating for a lowcalcium diet, para-cellular calcium transport becomes important with the increase in calcium content in the diet [1]. Paracellular transport occurs through the extracellular space between the layer of the epithelial cells in the intestine. Although it was previously thought that vitamin D does not affect para-cellular calcium absorption, studies conducted in recent years indicate otherwise, with vitamin D still affecting calcium absorption by increasing levels of various transmembrane and adhesion proteins that control the extracellular space between cells [78, 79]. However, it is not clear at what stage of the paracellular pathway these proteins are involved.

Phosphate, another important molecule for bone mineralization, is actively absorbed mostly in the jejunum, with absorption influenced by vitamin D [2]. This absorption is provided by sodium-phosphate co-transporter IIb (NaPi IIb). In experimental studies, it has been shown that phosphate absorption is blocked when cycloheximide, which inhibits protein synthesis, is given [80]. This situation supports that phosphate absorption occurs by genomic effect. Vitamin D increases NaPi-IIb expression and thus phosphate absorption [2].

**13**

turnover.

*Vitamin D Metabolism*

channels [1, 2, 82].

**4.3 The effect of vitamin D on bone tissue**

*DOI: http://dx.doi.org/10.5772/intechopen.97180*

**4.2 The effect of vitamin D on the kidneys**

Most of the calcium that reaches the kidney tubules is absorbed from the proximal and distal tubules and approximately 1–2% of it is excreted through urine. Approximately 65% of calcium absorption in the kidney is passively absorbed paracellularly from the proximal tubules with the sodium gradient and independent of vitamin D direct action [1]. The rest of the calcium is absorbed from the ascending limb of the loop of Henle (20%), the distal tubules (15–20%), and the collecting ducts (5%) [81]. Vitamin D plays an important role in calcium absorption in the distal tubules and provides active calcium absorption via the trans-cellular pathway with the help of an electrochemical gradient [1]. Calcium is taken into the cell by TRPV5 channel on the surface of the tubular cell and is transported inside the cell by calbindin-D9k and D28k. Transported to the basolateral part of the cell, calcium is released into the systemic circulation by NCX1 (sodium/calcium exchanger) and PMCA1b. This mechanism is similar to that in the intestinal tract. Vitamin D

increases the expression of TRPV5, calbindin, NCX and PMCA1b.

Phosphate is reabsorbed by sodium-dependent phosphate carrier proteins (NaPi-IIa and NaPi-IIc) in proximal tubular cells under vitamin D control. In addition, for phosphate reabsorption, a Na/K-ATPase channel located in the basolateral membrane is also needed [1, 2]. The impact of vitamin D on transport channels is not clearly known. While PTH increases the lysosomal degradation of phosphate transport channels, FGF23 causes a decrease in the expression of these

Calcium, phosphorus and vitamin D are important molecules for bone metabolism and health. Calcium is one of the most abundant minerals in the body and is obtained entirely from dietary sources. In addition to its various biological effects in the body, it is also essential for bone metabolism [83]. More than 99% of the total body calcium is found in the bone tissue as a calcium-phosphate mineral complex, while the remaining <1% is distributed between the intracellular and extracellular compartments [83]. While 40% of calcium outside bone tissue is bound to protein, 9% forms ionic complexes, and the remaining 51% is found as free ions [84, 85]. Ionized calcium balances the calcium pool in the intracellular-extracellular area and plays an important role in bone metabolism. This balance is provided by the cooperation of various hormones (PTH, vitamin D) and the organs they affect (kidney, bone and intestinal system) [83–85]. Where there is vitamin D deficiency (nutritional or genetic) or VDR-inactivating mutations, serum levels of calcium and phosphate, which play an important role in bone development and growth, are reduced and thus rickets/osteomalacia emerge. Rickets is a disease characterized by excessive osteoid tissue accumulation and defective mineralization of the epiphyseal plate, which occurs as a result of insufficient mineralization in the epiphyseal plates of growing bones [1, 2]. Osteomalacia is a disease characterized by a deterioration in the mineralization of the newly formed osteoid and a decrease in bone

There is a continuous remodeling cycle consisting bone tissue resorption and mineralization. When calcium, phosphorus, and vitamin D are sufficient, this cycle continues in a balanced manner. In the case of negative calcium balance caused by insufficient calcium intake with diet or increased renal calcium loss, vitamin D increases bone resorption in osteoblasts through VDR signaling, resulting in calcium passage from bone to blood, which leads to impaired bone mineralization. Vitamin D increases the expression of RANKL (receptor activator of NF-κB

*Vitamin D*

slowly [2].

diet is sufficient.

**4. Effects of Vitamin D on calcium and phosphorus**

One of the most important functions of vitamin D is to increase calcium absorption from the intestines. Calcium absorption from the intestinal tract occurs transcellular and para-cellular processes mediated through genomic and non-genomic effects. Among these, the trans-cellular pathway largely utilized by the intestinal system, which is regulated by vitamin D [2]. The absorption effect of vitamin D with non-genomic effect of calcium occurs directly on the membrane (transcaltachia). The channel-mediated calcium absorption effect of vitamin D occurs more

Calcium enters the epithelian cell by the effect of an electrical and chemical gradient via calcium channel protein TRPV6 (which has significant sequence homology to TRPV5 in the kidney), the transmembrane protein at the lumenal brush border edge of the intestinal epithelial cell. The expression of TRPV6 is activated by vitamin D [72]. Reduced intestinal calcium transport is observed in TRPV6 null mice [73]. Calcium entering the cell binds to calmodulin (CaM), which is bound with myosin 1A (also known as brush border myosin I). This formed complex allows calcium to be transported across the microvilli. Subsequently, the transport of calcium up to the basolateral membrane occurs inside the vesicle via calbindin-D9k (CaBP). The affinity of calcium for calbindinin is greater than for calmodulin, and better facilitates calcium transport inside the cell [74]. The calcium reaching the basolateral membrane is pumped out of the cell to systemic circulation via the Ca-ATPase (PMCA1b) pump located on the membrane [1, 2]. In addition, although it is less important, NCX (sodium/calcium exchanger), located in the basolateral region, also plays a role in excretion of calcium [2, 75]. Vitamin D shows its increasing effect on intestinal calcium absorption by inducing expression of TRPV6, CaBP

and PMCAb and increasing the binding affinity of CaM to myosin 1A [1, 2].

Intestinal calcium absorption, serum calcium level and bone mineral content in Kalbindin D9k null mice (regardless of dietary calcium level) have been shown to be similar to normal mice [76]. Intestinal calcium absorption was found to be normal in calbindin D9k and TRPV6 null mice when a diet containing the daily requirement for calcium was given [77]. These findings indicate there is a mechanism other than the genomic effect through which vitamin D exerts its action (a non-genomic effect) in calcium absorption in the intestines when the amount of calcium in the

While trans-cellular calcium absorption is effective in compensating for a lowcalcium diet, para-cellular calcium transport becomes important with the increase in calcium content in the diet [1]. Paracellular transport occurs through the extracellular space between the layer of the epithelial cells in the intestine. Although it was previously thought that vitamin D does not affect para-cellular calcium absorption, studies conducted in recent years indicate otherwise, with vitamin D still affecting calcium absorption by increasing levels of various transmembrane and adhesion proteins that control the extracellular space between cells [78, 79]. However, it is not

clear at what stage of the paracellular pathway these proteins are involved.

NaPi-IIb expression and thus phosphate absorption [2].

Phosphate, another important molecule for bone mineralization, is actively absorbed mostly in the jejunum, with absorption influenced by vitamin D [2]. This absorption is provided by sodium-phosphate co-transporter IIb (NaPi IIb). In experimental studies, it has been shown that phosphate absorption is blocked when cycloheximide, which inhibits protein synthesis, is given [80]. This situation supports that phosphate absorption occurs by genomic effect. Vitamin D increases

**4.1 Intestinal calcium absorption**

**12**

#### **4.2 The effect of vitamin D on the kidneys**

Most of the calcium that reaches the kidney tubules is absorbed from the proximal and distal tubules and approximately 1–2% of it is excreted through urine. Approximately 65% of calcium absorption in the kidney is passively absorbed paracellularly from the proximal tubules with the sodium gradient and independent of vitamin D direct action [1]. The rest of the calcium is absorbed from the ascending limb of the loop of Henle (20%), the distal tubules (15–20%), and the collecting ducts (5%) [81]. Vitamin D plays an important role in calcium absorption in the distal tubules and provides active calcium absorption via the trans-cellular pathway with the help of an electrochemical gradient [1]. Calcium is taken into the cell by TRPV5 channel on the surface of the tubular cell and is transported inside the cell by calbindin-D9k and D28k. Transported to the basolateral part of the cell, calcium is released into the systemic circulation by NCX1 (sodium/calcium exchanger) and PMCA1b. This mechanism is similar to that in the intestinal tract. Vitamin D increases the expression of TRPV5, calbindin, NCX and PMCA1b.

Phosphate is reabsorbed by sodium-dependent phosphate carrier proteins (NaPi-IIa and NaPi-IIc) in proximal tubular cells under vitamin D control. In addition, for phosphate reabsorption, a Na/K-ATPase channel located in the basolateral membrane is also needed [1, 2]. The impact of vitamin D on transport channels is not clearly known. While PTH increases the lysosomal degradation of phosphate transport channels, FGF23 causes a decrease in the expression of these channels [1, 2, 82].

#### **4.3 The effect of vitamin D on bone tissue**

Calcium, phosphorus and vitamin D are important molecules for bone metabolism and health. Calcium is one of the most abundant minerals in the body and is obtained entirely from dietary sources. In addition to its various biological effects in the body, it is also essential for bone metabolism [83]. More than 99% of the total body calcium is found in the bone tissue as a calcium-phosphate mineral complex, while the remaining <1% is distributed between the intracellular and extracellular compartments [83]. While 40% of calcium outside bone tissue is bound to protein, 9% forms ionic complexes, and the remaining 51% is found as free ions [84, 85]. Ionized calcium balances the calcium pool in the intracellular-extracellular area and plays an important role in bone metabolism. This balance is provided by the cooperation of various hormones (PTH, vitamin D) and the organs they affect (kidney, bone and intestinal system) [83–85]. Where there is vitamin D deficiency (nutritional or genetic) or VDR-inactivating mutations, serum levels of calcium and phosphate, which play an important role in bone development and growth, are reduced and thus rickets/osteomalacia emerge. Rickets is a disease characterized by excessive osteoid tissue accumulation and defective mineralization of the epiphyseal plate, which occurs as a result of insufficient mineralization in the epiphyseal plates of growing bones [1, 2]. Osteomalacia is a disease characterized by a deterioration in the mineralization of the newly formed osteoid and a decrease in bone turnover.

There is a continuous remodeling cycle consisting bone tissue resorption and mineralization. When calcium, phosphorus, and vitamin D are sufficient, this cycle continues in a balanced manner. In the case of negative calcium balance caused by insufficient calcium intake with diet or increased renal calcium loss, vitamin D increases bone resorption in osteoblasts through VDR signaling, resulting in calcium passage from bone to blood, which leads to impaired bone mineralization. Vitamin D increases the expression of RANKL (receptor activator of NF-κB

ligand), which is an osteoclastogenic factor from osteoblasts [86, 89]. RANKL stimulates osteoclastogenesis and increases osteoclast formation by binding to its related receptor, RANK [87]. In conclusion, in the case of negative calcium balance, vitamin D tries to keep the serum calcium level in a certain balance by increasing resorption and decreasing mineralization [1].

In the case of a positive calcium balance, the osteoblastogenic activity of vitamin D is prominent. In this situation where anti-resorbtive effect is in the predominant, bone mineral density increases. The occurrence of this effect has been associated with a decrease in the RANKL/OPG (osteoproteogerin) ratio and an increase in LRP-5 (LDL receptor related protein 5) expression [1]. LRP-5 is controlled by the VDR and is a necessary co-receptor for the anabolic effect of osteoblasts [88]. In addition, vitamin D plays a role in the proliferation of chondrocytes in the growth plate through genomic action.

#### **5. Regulation of vitamin D metabolism**

Pro-vitamin-D3, pre-vitamin D3 and then vitamin D3 (cholecalciferol) conversion in the skin is under the control of UV radiation. Serum vitamin D concentration reaches its highest level 24–48 hours after exposure to UV radiation and then shows a gradual decrease. The half-life of serum vitamin D is 36–72 hours. Vitamin D, which is a fat-soluble vitamin, is stored in adipose tissue for later use. The ability of vitamin D to be stored in adipose tissue extends its total half-life in the body up to approximately 2 months.

#### **5.1 Regulation of 25-hydroxylase**

There is little information on how this enzyme is regulated because of the few studies performed. What is known is that serum vitamin D level is inversely related to the rate of 25-hydroxylation in the liver, and the synthesis of 25OHD3 from vitamin D (cholecalciferol) is regulated by the 25-hydroxylase enzyme**.** This activity of the enzyme is directly inhibited by 25OHD3. Consequently, serum 25OHD3 levels can be kept at a physiological window ranging from 75 to 220 nmol/L (30–88 ng/ mL). However, when an overdose of vitamin D is taken orally, this inhibitory mechanism in 25OHD3 synthesis cannot prevent vitamin D intoxication [2].

#### **5.2 Regulation of renal 1-alpha hydroxylation**

Serum active vitamin D levels in healthy adults vary within extremely narrow ranges, so that even in cases of vitamin D intoxication, serum levels may remain normal. 1-alpha hydroxylation activity in the kidney is controlled by PTH, calcium and phosphorus. Hypocalcemia, increased PTH, and hypophosphatemia will stimulate increases in active vitamin D production through renal 1-alpha hydroxylase enzyme activation, while hypercalcemia, FGF-23 secreted from osteoblasts, and active vitamin D itself have an inhibitory effect on active vitamin D synthesis through the renal 1-alpha hydroxylase enzyme. Active vitamin D increases FGF23 synthesis from osteoblasts. FGF23 suppresses the 1-alpha hydroxylase enzyme and increases the activity of 24 hydroxylase enzymes. In addition, hypercalcemia suppressing PTH and hyperphosphatemia by increasing FGF23 levels results in 1-alpha hydroxylase enzyme activity inhbition [1–3]. It is also suggested that calcium and phosphate have a direct regulatory effect on 1-alpha hydroxylase enzyme [89].

Calcitonin is known to reduce serum calcium levels through osteoclast inhibition. In addition, this hormone has been shown to increase the expression of

**15**

*Vitamin D Metabolism*

demand of the body [1, 91].

25OHD3 and active vitamin D levels.

**5.3 Regulation of 24-alpha hydroxylase**

through alternative catabolism [1, 2, 93].

**6. Vitamin D measurement methods**

*DOI: http://dx.doi.org/10.5772/intechopen.97180*

CYP27B1, the gene encoding the 1-alpha hydroxylase enzyme, in normocalcemic pregnant women due to the increase in calcium need. In this way, active vitamin D synthesis and consequently intestinal calcium absorption is increased [1, 90]. Apart from calcitonin, it has been suggested that prolactin also increases CYP27B1 expression, especially during lactation, and thus contributes to the increased calcium

CYP3A4 enzyme in the liver and intestinal system has also been shown to be effective in the inactivation of 25OHD3 and reduction of active vitamin D [92]. Long-term use of drugs such as phenytoin, rifampicin, and carbamazepine may lead to up-regulation of the CYP3A4 enzyme and thus to a decrease in serum

When serum calcium, phosphate and PTH levels are within normal levels, 25OHD3 and 1–25 (OH) 2 D3 are metabolized into biologically inactive forms by activation of 24-alpha hydroxylase enzyme in the kidneys (24–25 dihydroxy vitamin D3 and 1,24, 25 trihydroxy vitamin D3). This enzyme preferably binds to 1–25 (OH) 2 D3, thus limiting the effect of active vitamin D in tissues through inactivation [2]. The low level of 24-hydroxylase enzyme activity leads to high levels of 1–25 (OH) 2D3 and thus hypercalcemia. In addition, it has been suggested that a decrease in this enzyme activity may lead to impairment in intra-membranous bone mineralization [1, 2]. On the other hand, when 1–25 (OH) 2 D3 synthesis decreases, 1-alpha hydroxylase enzyme activity increases and 24-hydroxylase enzyme activity decreases. It is also known that FGF23 increases the activity of 24 hydroxylase enzymes [1, 2].

**5.4 Regulation of active vitamin D synthesis in extra-renal tissues**

Numerous studies have shown active vitamin D synthesis by 1-alpha hydroxylase enzyme is not only a renal feature [2, 93]. The gene encoding the 1-alpha hydroxylase enzyme and the vitamin D receptor gene can be expressed in many cells or tissues such as skin, placenta, prostate, parathyroid, bone tissue, colon, lung, breast tissue, monocytes and macrophages, as well as renal cells. It has been reported that active vitamin D synthesized in the aforementioned tissues functions mostly as an intracrine or paracrine factor in the tissues where they are located, and does not contribute to the active vitamin D levels in the circulation, except for some special cases [1, 2]. Since PTH and FGF-23 receptors are not found in these tissues, they are not directly involved in controlling active vitamin D synthesis. However, it is propable that PTH increases the effect of vitamin D through posttranscriptional modification [31]. Unlike in other tissues, in activated macrophages, there is also no negative feedback of active vitamin D on 1-alpha hydroxylase enzyme [91]. Moreover, although the 24-hydroxylase enzyme is expressed in these cells, its function is not fully understood. Cytokines such as IL-1, TNF-α, IFN-γ induce the synthesis of active vitamin D in keratinocytes. Unlike macrophages, keratinocytes have a fully functional 24-hydroxylase enzyme activity and is induced by active vitamin D. In this way, active vitamin D limits its own synthesis in the epidermis

Measurement of serum levels of vitamin D, which plays an important role in calcium and phosphorus metabolism and bone mineralization, is routinely performed

#### *Vitamin D Metabolism DOI: http://dx.doi.org/10.5772/intechopen.97180*

*Vitamin D*

ligand), which is an osteoclastogenic factor from osteoblasts [86, 89]. RANKL stimulates osteoclastogenesis and increases osteoclast formation by binding to its related receptor, RANK [87]. In conclusion, in the case of negative calcium balance, vitamin D tries to keep the serum calcium level in a certain balance by increasing

In the case of a positive calcium balance, the osteoblastogenic activity of vitamin D is prominent. In this situation where anti-resorbtive effect is in the predominant, bone mineral density increases. The occurrence of this effect has been associated with a decrease in the RANKL/OPG (osteoproteogerin) ratio and an increase in LRP-5 (LDL receptor related protein 5) expression [1]. LRP-5 is controlled by the VDR and is a necessary co-receptor for the anabolic effect of osteoblasts [88]. In addition, vitamin D plays a role in the proliferation of chondrocytes in the growth

Pro-vitamin-D3, pre-vitamin D3 and then vitamin D3 (cholecalciferol) conversion in the skin is under the control of UV radiation. Serum vitamin D concentration reaches its highest level 24–48 hours after exposure to UV radiation and then shows a gradual decrease. The half-life of serum vitamin D is 36–72 hours. Vitamin D, which is a fat-soluble vitamin, is stored in adipose tissue for later use. The ability of vitamin D to be stored in adipose tissue extends its total half-life in the body up to

There is little information on how this enzyme is regulated because of the few studies performed. What is known is that serum vitamin D level is inversely related to the rate of 25-hydroxylation in the liver, and the synthesis of 25OHD3 from vitamin D (cholecalciferol) is regulated by the 25-hydroxylase enzyme**.** This activity of the enzyme is directly inhibited by 25OHD3. Consequently, serum 25OHD3 levels can be kept at a physiological window ranging from 75 to 220 nmol/L (30–88 ng/ mL). However, when an overdose of vitamin D is taken orally, this inhibitory mechanism in 25OHD3 synthesis cannot prevent vitamin D intoxication [2].

Serum active vitamin D levels in healthy adults vary within extremely narrow ranges, so that even in cases of vitamin D intoxication, serum levels may remain normal. 1-alpha hydroxylation activity in the kidney is controlled by PTH, calcium and phosphorus. Hypocalcemia, increased PTH, and hypophosphatemia will stimulate increases in active vitamin D production through renal 1-alpha hydroxylase enzyme activation, while hypercalcemia, FGF-23 secreted from osteoblasts, and active vitamin D itself have an inhibitory effect on active vitamin D synthesis through the renal 1-alpha hydroxylase enzyme. Active vitamin D increases FGF23 synthesis from osteoblasts. FGF23 suppresses the 1-alpha hydroxylase enzyme and increases the activity of 24 hydroxylase enzymes. In addition, hypercalcemia suppressing PTH and hyperphosphatemia by increasing FGF23 levels results in 1-alpha hydroxylase enzyme activity inhbition [1–3]. It is also suggested that calcium and phosphate have a direct regulatory effect on 1-alpha hydroxylase enzyme [89]. Calcitonin is known to reduce serum calcium levels through osteoclast inhibition. In addition, this hormone has been shown to increase the expression of

resorption and decreasing mineralization [1].

**5. Regulation of vitamin D metabolism**

plate through genomic action.

approximately 2 months.

**5.1 Regulation of 25-hydroxylase**

**5.2 Regulation of renal 1-alpha hydroxylation**

**14**

CYP27B1, the gene encoding the 1-alpha hydroxylase enzyme, in normocalcemic pregnant women due to the increase in calcium need. In this way, active vitamin D synthesis and consequently intestinal calcium absorption is increased [1, 90]. Apart from calcitonin, it has been suggested that prolactin also increases CYP27B1 expression, especially during lactation, and thus contributes to the increased calcium demand of the body [1, 91].

CYP3A4 enzyme in the liver and intestinal system has also been shown to be effective in the inactivation of 25OHD3 and reduction of active vitamin D [92]. Long-term use of drugs such as phenytoin, rifampicin, and carbamazepine may lead to up-regulation of the CYP3A4 enzyme and thus to a decrease in serum 25OHD3 and active vitamin D levels.

#### **5.3 Regulation of 24-alpha hydroxylase**

When serum calcium, phosphate and PTH levels are within normal levels, 25OHD3 and 1–25 (OH) 2 D3 are metabolized into biologically inactive forms by activation of 24-alpha hydroxylase enzyme in the kidneys (24–25 dihydroxy vitamin D3 and 1,24, 25 trihydroxy vitamin D3). This enzyme preferably binds to 1–25 (OH) 2 D3, thus limiting the effect of active vitamin D in tissues through inactivation [2]. The low level of 24-hydroxylase enzyme activity leads to high levels of 1–25 (OH) 2D3 and thus hypercalcemia. In addition, it has been suggested that a decrease in this enzyme activity may lead to impairment in intra-membranous bone mineralization [1, 2]. On the other hand, when 1–25 (OH) 2 D3 synthesis decreases, 1-alpha hydroxylase enzyme activity increases and 24-hydroxylase enzyme activity decreases. It is also known that FGF23 increases the activity of 24 hydroxylase enzymes [1, 2].

#### **5.4 Regulation of active vitamin D synthesis in extra-renal tissues**

Numerous studies have shown active vitamin D synthesis by 1-alpha hydroxylase enzyme is not only a renal feature [2, 93]. The gene encoding the 1-alpha hydroxylase enzyme and the vitamin D receptor gene can be expressed in many cells or tissues such as skin, placenta, prostate, parathyroid, bone tissue, colon, lung, breast tissue, monocytes and macrophages, as well as renal cells. It has been reported that active vitamin D synthesized in the aforementioned tissues functions mostly as an intracrine or paracrine factor in the tissues where they are located, and does not contribute to the active vitamin D levels in the circulation, except for some special cases [1, 2]. Since PTH and FGF-23 receptors are not found in these tissues, they are not directly involved in controlling active vitamin D synthesis. However, it is propable that PTH increases the effect of vitamin D through posttranscriptional modification [31]. Unlike in other tissues, in activated macrophages, there is also no negative feedback of active vitamin D on 1-alpha hydroxylase enzyme [91]. Moreover, although the 24-hydroxylase enzyme is expressed in these cells, its function is not fully understood. Cytokines such as IL-1, TNF-α, IFN-γ induce the synthesis of active vitamin D in keratinocytes. Unlike macrophages, keratinocytes have a fully functional 24-hydroxylase enzyme activity and is induced by active vitamin D. In this way, active vitamin D limits its own synthesis in the epidermis through alternative catabolism [1, 2, 93].

#### **6. Vitamin D measurement methods**

Measurement of serum levels of vitamin D, which plays an important role in calcium and phosphorus metabolism and bone mineralization, is routinely performed worldwide. For this, it is preferred to measure the 25OHD level, which has a longer half-life (24–36 hours), can be taken exogenously, and can be synthesized endogenously. The half-life of the 1–25 (OH) 2D3 form is short (4–6 hours), and its serum levels are 1000 times lower than 25OHD. For these reasons, the active form is not preferred for routine measurement. In this section, the measurement methods of 25OHD vitamin are discussed.

To date, many methods have been developed for measuring serum vitamin D levels. These methods are basically divided into two groups. One methodology is the use of competitive binding and immunoassays: radioimmunoassay (RIA), enzyme immunoassay (EIA/ELISA), chemiluminescent immunoassay (CLIA), electrochemiluminescence assay (ECLIA), and competitive protein binding assay. The other methodology involves chemical methods. Chemical methods are based on the non-immunological direct detection methods typically after preparative chromatographic separation. Chemical methods include high performance liquid chromatography (HPLC) and LC/MS (liquid chromatography-mass spectrometer).

The first method used in the measurement of vitamin D is the competitive binding method in which VDBP binds. This method was first reported in 1971 and identifies 25OHD2 and 25OHD3 forms equally [94]. Limitations of this method include the incubation period of 10 days and its inability to separate some polar vitamin D metabolites [24,25(OH)2D, 25,26 (OH)2D ve 25,26 (OH)2D-26,23--lactone] [94]. In the late 1970s, the HPLC method was developed that can exclude the effect of polar vitamin D metabolites causing interference to the chromatographic method [95]. The advantages of this method, which uses a UV absorption technique, include the absence of lipid and polar vitamin D metabolite interference, the ability to measure 25OHD2 and 25OHD3 separated at high resolution, and a high specificity and reliability. Its disadvantages include the use of excess sample amounts, equipment cost, a need for preparative chromatography, and interference by other UV-absorbing compounds, and that the method is somewhat complex and not easily practical. It would not be considered a routine diagnostic test, as it is used in only about 2% of laboratories in the world) [94, 95]. With the later development of the RIA method, the value of quantifying vitamin levels improved. The advantages of this method type are that sample amount can be small and not pre-analytical preparative purification process is required. The assay is economical and easily applicable, and results reliable. As to the disadvantages, chemical and radioactive (with the RIA) waste are issues, and there is cross-reactivity with polar vitamin D metabolites as in the earlier competitive binding type assays. The RIA also is 100% specific for 25OHD3 and 75% specific for 25OHD2, so the final calculation requires an adjustment [94, 96]. Nonetheless automated immunoassay methods are widely used in our country and all over the world (approximately 76% of laboratories in the world) [97]. Requiring less sample volume, not requiring sample preparation, easy equipment supply, easy application, fast results, no cross-reactivity with C3-epimer forms, and low user error are among the reasons why this method is used more widely in the world [97, 98]. Despite its widespread use, this method has some significant disadvantages. In this method, 25OHD2 and 25OHD3 cannot be distinguished and both are measured as total of 25OHD. This may lead to misinterpretation in countries that use ergocalciferol in treatment (eg America) [97]. In addition, automated immunoassay results can be affected by pregnancy, whether sampled from intensive care patients, the presence of chronic disease and liver diseases, all of which affect the amount of VDBP synthesized from the liver [99, 100]. In addition, it has been reported that there is a high probability of interferences involving automated immunoassay measurement methods [97, 101].

Due to the low reliability of immunoassay measurements, this method has begun to be replaced by LC–MS/MS, which is considered to be the "gold standard"

**17**

**Author details**

Sezer Acar and Behzat Özkan\*

provided the original work is properly cited.

Division of Pediatric Endocrinology, University of Health Science, Dr. Behçet Uz Child Disease and Pediatric Surgery Training and Research, Izmir, Turkey

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: ozkan.behzat@gmail.com

forms of vitamin D are not yet suitable for routine use.

*Vitamin D Metabolism*

interference [97, 102].

*DOI: http://dx.doi.org/10.5772/intechopen.97180*

method. This method is used in approximately 18% of laboratories around the world, and it is estimated that its prevalence will increase due to its more accurate and precise results [97]. This method provides distinguishing quantitative measurements of both 25OHD2 and 25OHD3 forms in both serum and plasma [102]. Hence, 25OHD2 can be easily monitored in countries where ergocalciferol is widely used. In addition, with this method, C-3 epimer forms of vitamin D, which are present in high levels in serum in the first year, can be separated from other forms, and these metabolites are prevented from causing vitamin D measurement

In recent years, instead of measuring the level of vitamin D bound to VDBP, there is a strong belief in the need to measure free vitamin D levels as that is the form that accounts for the principal bioactivity. Routine methods measure the level of 25OHD vitamin bound to VDBP and provide information about the total body pool. In parallel with this, if the total body pool is sufficient, free vitamin D level is estimated to be sufficient. However, the situation is somewhat complex in obese patients, where a negative correlation between the amount of adipose tissue and serum vitamin D levels has been reported. In these cases, it has been reported that serum 25OHD level is lower than those with normal body weight, since large adipose tissue creates a larger pool for vitamin D sequestration [101–105]. In other words, serum 25OHD level in obese patients may not provide information about the body pool of vitamin D. It is thought that it would be more valuable to measure vitamin D levels that are not bound to binding protein in these cases. However, there is a serious standardization problem in the measurement of free 25OHD [103]. Also, Bikle et al. [106] proposed a method by which free 25OHD vitamin can be calculated. However, studies have shown that the results obtained with this method are not reliable [107]. Finally, direct measurement or indirect calculations of free

#### *Vitamin D Metabolism DOI: http://dx.doi.org/10.5772/intechopen.97180*

*Vitamin D*

25OHD vitamin are discussed.

worldwide. For this, it is preferred to measure the 25OHD level, which has a longer half-life (24–36 hours), can be taken exogenously, and can be synthesized endogenously. The half-life of the 1–25 (OH) 2D3 form is short (4–6 hours), and its serum levels are 1000 times lower than 25OHD. For these reasons, the active form is not preferred for routine measurement. In this section, the measurement methods of

To date, many methods have been developed for measuring serum vitamin D levels. These methods are basically divided into two groups. One methodology is the use of competitive binding and immunoassays: radioimmunoassay (RIA), enzyme immunoassay (EIA/ELISA), chemiluminescent immunoassay (CLIA), electrochemiluminescence assay (ECLIA), and competitive protein binding assay. The other methodology involves chemical methods. Chemical methods are based on the non-immunological direct detection methods typically after preparative chromatographic separation. Chemical methods include high performance liquid chromatography (HPLC) and LC/MS (liquid chromatography-mass spectrometer). The first method used in the measurement of vitamin D is the competitive binding method in which VDBP binds. This method was first reported in 1971 and identifies 25OHD2 and 25OHD3 forms equally [94]. Limitations of this method include the incubation period of 10 days and its inability to separate some polar vitamin D metabolites [24,25(OH)2D, 25,26 (OH)2D ve 25,26 (OH)2D-26,23--lactone] [94]. In the late 1970s, the HPLC method was developed that can exclude the effect of polar vitamin D metabolites causing interference to the chromatographic method [95]. The advantages of this method, which uses a UV absorption technique, include the absence of lipid and polar vitamin D metabolite interference, the ability to measure 25OHD2 and 25OHD3 separated at high resolution, and a high specificity and reliability. Its disadvantages include the use of excess sample amounts, equipment cost, a need for preparative chromatography, and interference by other UV-absorbing compounds, and that the method is somewhat complex and not easily practical. It would not be considered a routine diagnostic test, as it is used in only about 2% of laboratories in the world) [94, 95]. With the later development of the RIA method, the value of quantifying vitamin levels improved. The advantages of this method type are that sample amount can be small and not pre-analytical preparative purification process is required. The assay is economical and easily applicable, and results reliable. As to the disadvantages, chemical and radioactive (with the RIA) waste are issues, and there is cross-reactivity with polar vitamin D metabolites as in the earlier competitive binding type assays. The RIA also is 100% specific for 25OHD3 and 75% specific for 25OHD2, so the final calculation requires an adjustment [94, 96]. Nonetheless automated immunoassay methods are widely used in our country and all over the world (approximately 76% of laboratories in the world) [97]. Requiring less sample volume, not requiring sample preparation, easy equipment supply, easy application, fast results, no cross-reactivity with C3-epimer forms, and low user error are among the reasons why this method is used more widely in the world [97, 98]. Despite its widespread use, this method has some significant disadvantages. In this method, 25OHD2 and 25OHD3 cannot be distinguished and both are measured as total of 25OHD. This may lead to misinterpretation in countries that use ergocalciferol in treatment (eg America) [97]. In addition, automated immunoassay results can be affected by pregnancy, whether sampled from intensive care patients, the presence of chronic disease and liver diseases, all of which affect the amount of VDBP synthesized from the liver [99, 100]. In addition, it has been reported that there is a high probability of interferences involving automated immunoassay

**16**

measurement methods [97, 101].

Due to the low reliability of immunoassay measurements, this method has begun to be replaced by LC–MS/MS, which is considered to be the "gold standard" method. This method is used in approximately 18% of laboratories around the world, and it is estimated that its prevalence will increase due to its more accurate and precise results [97]. This method provides distinguishing quantitative measurements of both 25OHD2 and 25OHD3 forms in both serum and plasma [102]. Hence, 25OHD2 can be easily monitored in countries where ergocalciferol is widely used. In addition, with this method, C-3 epimer forms of vitamin D, which are present in high levels in serum in the first year, can be separated from other forms, and these metabolites are prevented from causing vitamin D measurement interference [97, 102].

In recent years, instead of measuring the level of vitamin D bound to VDBP, there is a strong belief in the need to measure free vitamin D levels as that is the form that accounts for the principal bioactivity. Routine methods measure the level of 25OHD vitamin bound to VDBP and provide information about the total body pool. In parallel with this, if the total body pool is sufficient, free vitamin D level is estimated to be sufficient. However, the situation is somewhat complex in obese patients, where a negative correlation between the amount of adipose tissue and serum vitamin D levels has been reported. In these cases, it has been reported that serum 25OHD level is lower than those with normal body weight, since large adipose tissue creates a larger pool for vitamin D sequestration [101–105]. In other words, serum 25OHD level in obese patients may not provide information about the body pool of vitamin D. It is thought that it would be more valuable to measure vitamin D levels that are not bound to binding protein in these cases. However, there is a serious standardization problem in the measurement of free 25OHD [103]. Also, Bikle et al. [106] proposed a method by which free 25OHD vitamin can be calculated. However, studies have shown that the results obtained with this method are not reliable [107]. Finally, direct measurement or indirect calculations of free forms of vitamin D are not yet suitable for routine use.

### **Author details**

Sezer Acar and Behzat Özkan\* Division of Pediatric Endocrinology, University of Health Science, Dr. Behçet Uz Child Disease and Pediatric Surgery Training and Research, Izmir, Turkey

\*Address all correspondence to: ozkan.behzat@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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**19**

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25-hydroxylase. Proc Natl Acad Sci U S

cholestane-3 alpha, 7 alpha, 12 alpha-

[22] Fu GK, Portale AA, Miller WL. Complete structure of the human gene for the vitamin D 1alpha-hydroxylase,

[23] Fu GK, Lin D, Zhang MY, et al. Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets

[24] Shinki T, Ueno Y, DeLuca HF, Suda T. Calcitonin is a major regulator

hydroxylase gene in normocalcemic rats.

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[18] Moghadasian MH. Cerebrotendinous xanthomatosis: clinical course, genotypes and metabolic backgrounds. Clin Invest Med. 2004; 27(1):42-50.

[19] Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW. De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem. 2003;278(39):38084-93.

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[24] Shinki T, Ueno Y, DeLuca HF, Suda T. Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D3-1alphahydroxylase gene in normocalcemic rats. Proc Natl Acad Sci U S A. 1999;96(14):8253-8.

[25] Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S. 25-Hydroxyvitamin D3 1alphahydroxylase and vitamin D synthesis. Science. 1997;277(5333):1827-30.

[26] St-Arnaud R, Messerlian S, Moir JM, Omdahl JL, Glorieux FH. The 25-hydroxyvitamin D 1-alphahydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. J Bone Miner Res. 1997;12(10):1552-9.

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[29] Barbour GL, Coburn JW, Slatopolsky E, Norman AW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Med. 1981;305(8):440-3.

[30] Bosch X. Hypercalcemia due to endogenous overproduction of 1,25-dihydroxyvitamin D in Crohn's disease. Gastroenterology. 1998;114(5):1061-5.

[31] Flanagan JN, Wang L, Tangpricha V, Reichrath J, Chen TC, Holick MF. Regulation of the 25- hydroxyvitamin D-1alpha-hydroxylase gene and its splice variant. Recent Results Cancer Res. 2003;164:157-167.

[32] Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. Arch Biochem Biophys. 2012;523(1):9-18.

[33] Shima M, Tanaka H, Norman AW, et al. 23(S),25(R)-1,25-dihydroxyvitamin D3-26,23-lactone stimulates murine bone formation in vivo. Endocrinology. 1990;126(2):832-6.

[34] Plachot JJ, Du Bois MB, Halpern S, Cournot-Witmer G, Garabedian M,

**18**

*Vitamin D*

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[10] Matsuoka LY, Wortsman J, Dannenberg MJ, Hollis BW, Lu Z, Holick MF. Clothing prevents ultraviolet-B radiation-dependent photosynthesis of vitamin D3. J Clin Endocrinol Metab. 1992;75(4):1099-103.

[11] Matsuoka LY, Ide L, Wortsman J, MacLaughlin JA, Holick MF. Sunscreens

suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab.

[12] Bell NH, Greene A, Epstein S, Oexmann MJ, Shaw S, Shary J. Evidence

D-endocrine system in blacks. J Clin

[13] Holick MF. Environmental factors that influence the cutaneous production of vitamin D. Am J Clin Nutr. 1995;61

[14] Holick MF. Vitamin D: A D-lightful solution for health. J Investig Med.

[15] Heaney RP, Horst RL, Cullen DM, Armas LA. Vitamin D distribution and status in the body. J Am Coll Nutr.

[16] Zhu J, DeLuca HF. Vitamin D 25-hydroxylase: four decades of searching, are we there yet? Arch Biochem Biophys. 2012;523(1):30-6.

[17] Zhu JG, Ochalek JT, Kaufmann M, Jones G, Deluca HF. CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in

vivo. Proc Natl Acad Sci 2013;110(39):15650-5.

for alteration of the vitamin

Invest. 1985;76(2):470-3.

(3 Suppl):638-45.

2011;59(6):872-80.

2009;28(3):252-6.

1987;64(6):1165-8.

1980;210(4466):203-5.

[2] Bikle DD. Vitamin D metabolism,

[3] Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr.

equilibrium and disequilibrium assay

Ramberg CF, Koszewski NJ, Napoli JL.

[6] Tripkovic L, Lambert H, Hart K, et al. Comparison of vitamin D2 and vitamin D3supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 2012;95(6):1357-64.

[7] Bikle D. Vitamin D: Production, Metabolism, and Mechanisms of Action. [Updated 2017 Aug 11]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm. nih.gov/books/NBK278935/ (accessed

on 20 January 2020)

[8] Holick MF. The cutaneous photosynthesis of previtamin D3: a unique photoendocrine system. J Invest

Dermatol. 1981;77(1):51-8.

[4] Hollis BW. Comparison of

conditions for ergocalciferol, cholecalciferol and their major metabolites. J Steroid Biochem.

[5] Horst RL, Reinhardt TA,

24-Hydroxylation of 1,25 dihydroxyergocalciferol. An unambiguous deactivation process. J Biol Chem. 1986; 261(20):9250-6.

Rev 2016;96(1):365-408.

mechanism of action, and clinicalapplications. Chem Biol.

2014;21(3):319-29.

2006; 84(4):694-7.

1984;21(1):81-6.

Balsan S. In vitro action of 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol on matrix organization and mineral distribution in rabbit growth plate. Metab Bone Dis Relat Res. 1982;4(2):135-42.

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[42] Madden K, Feldman HA, Chun RF, et al. Critically Ill Children Have Low Vitamin DBinding Protein, Influencing Bioavailability of Vitamin D. Ann Am Thorac Soc. 2015;12(11):1654-61.

[43] Zella LA, Shevde NK, Hollis BW, Cooke NE, Pike JW. Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo. Endocrinology. 2008;149(7):3656-67.

[44] Safadi FF, Thornton P, Magiera H, et al. Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J Clin Invest. 1999;103(2):239-51.

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[46] Bouillon R, van Baelen H, de Moor P. Comparative study of the affinity of the serum vitamin D-binding protein. J Steroid Biochem. 1980;13(9):1029-34

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**21**

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*Vitamin D Metabolism DOI: http://dx.doi.org/10.5772/intechopen.97180*

receptor binding determinants but constitute functionally distinct complexes. Mol Cell Biol. 2000;20(8):2718-26.

*Vitamin D*

Balsan S. In vitro action of

Metab Bone Dis Relat Res.

1982;4(2):135-42.

function in the rat 1,25-dihydroxyvitamin D

1995;270(4):1675-8.

1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol on matrix organization and mineral distribution in rabbit growth plate. [42] Madden K, Feldman HA, Chun RF, et al. Critically Ill Children Have Low Vitamin DBinding Protein, Influencing Bioavailability of Vitamin D. Ann Am Thorac Soc. 2015;12(11):1654-61.

[43] Zella LA, Shevde NK, Hollis BW, Cooke NE, Pike JW. Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo. Endocrinology. 2008;149(7):3656-67.

[44] Safadi FF, Thornton P, Magiera H, et al. Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J Clin Invest.

[45] Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP).

Hum Genet. 1993;92(2):183-8.

protein. J Steroid Biochem.

1980;13(9):1029-34

[46] Bouillon R, van Baelen H, de Moor P. Comparative study of the affinity of the serum vitamin D-binding

[47] Cantorna MT. Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease. Prog Biophys Mol Biol. 2006;92(1):60-4.

[48] Margolis RN, Christakos S. The nuclear receptor superfamily of steroid

[49] Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand.

[50] Rachez C, Gamble M, Chang CP, Atkins GB, Lazar MA, Freedman LP. The DRIP complex and SRC-1/p160 coactivators share similar nuclear

hormones and vitamin D gene regulation. An update. Ann N Y Acad

Sci. 2010;1192:208-14.

Mol Cell. 2000;5(1):173-9.

1999;103(2):239-51.

[35] Zierold C, Darwish HM, DeLuca HF. Two vitamin D response elements

24-hydroxylase promoter. J Biol Chem.

[36] Inoue Y, Segawa H, Kaneko I, et al. Role of the vitamin D receptor in FGF23 action on phosphate metabolism. Biochem J. 2005;390(Pt 1):325-31.

[37] Schlingmann KP, Kaufmann M,

Yazdanpanah M, Adeli K. Analytical measurement and clinical relevance of vitamin D(3) C3-epimer. Clin Biochem.

Hatakeyama S, et al. C-3 epimerization of vitamin D3 metabolites and further

25-hydroxyvitamin D3 is metabolized to 3-epi-25-hydroxyvitamin D3 and subsequently metabolized through C-1alpha or C-24 hydroxylation. J Biol Chem. 2004;279(16):15897-907.

[40] Cooke NE, Haddad JG. Vitamin D binding protein (Gc-globulin). Endocr

[41] Bikle DD, Halloran BP, Gee E,

levels. J Clin Invest. 1986;78(3):

Weber S, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med. 2011 Aug

[38] ailey D, Veljkovic K,

2013 Feb;46(3):190-6.

[39] Kamao M, Tatematsu S,

metabolism of C-3 epimers:

Rev. 1989;10(3):294-307.

Ryzen E, Haddad JG. Free 25-hydroxyvitamin D levels are normal in subjects with liver disease and reduced total 25-hydroxyvitamin D

4;365(5):410-21.

**20**

748-52.

[51] Orlov I, Rochel N, Moras D, Klaholz BP. Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA. EMBO J. 2012;31(2):291-300.

[52] Chen S, Cui J, Nakamura K, Ribeiro RC, West BL, Gardner DG. Coactivator-vitamin D receptor interactions mediate inhibition of the atrial natriuretic peptide promoter. J Biol Chem. 2000;275(20):15039-48.

[53] Haussler MR, Whitfield GK, Haussler CA, et al. 1,25-Dihydroxyvitamin D and Klotho: A Tale of Two Renal Hormones Coming of Age. Vitam Horm. 2016;100:165-230.

[54] Haussler MR, Whitfield GK, Kaneko I, et al. Molecular mechanisms of vitamin D action. Calcif Tissue Int. 2013;92(2):77-98.

[55] Essa S, Denzer N, Mahlknecht U, et al. VDR microRNA expression and epigenetic silencing of vitamin D signaling in melanoma cells. J Steroid Biochem Mol Biol. 2010;121(1-2):110-3.

[56] Yin JW, Wang G. The Mediator complex: a master coordinator of transcription and cell lineage development. Development. 2014;141(5):977-87.

[57] Caffrey JM, Farach-Carson MC. Vitamin D3 metabolites modulate dihydropyridine-sensitive calcium currents in clonal rat osteosarcoma cells. J Biol Chem. 1989;264(34):20265-74.

[58] Baran DT, Sorensen AM, Honeyman TW, Ray R, Holick MF. 1 alpha,25-dihydroxyvitamin D3-induced increments in hepatocyte cytosolic calcium and lysophosphatidylinositol: inhibition by pertussis toxin and 1

beta,25-dihydroxyvitamin D3. J Bone Miner Res. 1990;5(5):517-24.

[59] Morelli S, de Boland AR, Boland RL. Generation of inositol phosphates, diacylglycerol and calcium fluxes in myoblasts treated with 1,25-dihydroxyvitamin D3. Biochem J. 1993 Feb 1;289 ( Pt 3):675-9.

[60] Wali RK, Baum CL, Sitrin MD, Brasitus TA. 1,25(OH)2 vitamin D3 stimulates membrane phosphoinositide turnover, activates protein kinase C, and increases cytosolic calcium in rat colonic epithelium. J Clin Invest. 1990;85(4):1296-303.

[61] Khare S, Bolt MJ, Wali RK, et al. 1,25 dihydroxyvitamin D3 stimulates phospholipase C-gamma in rat colonocytes: role of c-Src in PLCgamma activation. J Clin Invest. 1997;99(8):1831-41.

[62] Revelli A, Massobrio M, Tesarik J. Nongenomic effects of 1alpha,25 dihydroxyvitamin D(3). Trends Endocrinol Metab. 1998;9(10):419-27.

[63] Nemere I, Yoshimoto Y, Norman AW. Calcium transport in perfused duodena from normal chicks: enhancement within fourteen minutes of exposure to 1,25-dihydroxyvitamin D3. Endocrinology. 1984;115(4):1476-83.

[64] Nemere I, Norman AW. Rapid action of 1,25-dihydroxyvitamin D3 on calcium transport in perfused chick duodenum: effect of inhibitors. J Bone Miner Res.1987;2(2):99-107.

[65] de Boland AR, Norman AW. Influx of extracellular calcium mediates 1,25-dihydroxyvitamin D3-dependent transcaltachia (the rapid stimulation of duodenal Ca2+ transport). Endocrinology. 1990;127(5):2475-80.

[66] de Boland AR, Norman A. Evidence for involvement of protein kinase C and cyclic adenosine 3',5'

monophosphate-dependent protein kinase in the 1,25-dihydroxy-vitamin D3-mediated rapid stimulation of intestinal calcium transport, (transcaltachia). Endocrinology. 1990;127(1):39-45.

[67] Norman AW, Okamura WH, Hammond MW, et al. Comparison of 6-s-cis- and 6-s-trans-locked analogs of 1alpha,25-dihydroxyvitamin D3 indicates that the 6-s-cis conformation is preferred for rapid nongenomic biological responses and that neither 6-s-cis- nor 6-s-trans-locked analogs are preferred for genomic biological responses. Mol Endocrinol. 1997;11(10):1518-31.

[68] Sequeira VB, Rybchyn MS, Tongkao-On W, et al. The role of the vitamin D receptor and ERp57 in photoprotection by 1α,25 dihydroxyvitamin D3. Mol Endocrinol. 2012;26(4):574-82.

[69] Mizwicki MT, Norman AW. The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling. Sci Signal. 2009;2(75):re4.

[70] Nemere I, Farach-Carson MC, Rohe B, et al. Ribozyme knockdown functionally links a 1,25(OH)2D3 membrane binding protein (1,25D3-MARRS) and phosphate uptake in intestinal cells. Proc Natl Acad Sci U S A. 2004;101(19):7392-7.

[71] Huhtakangas JA, Olivera CJ, Bishop JE, Zanello LP, Norman AW. The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha,25(OH)2-vitamin D3 in vivo and in vitro. Mol Endocrinol. 2004;18(11):2660-71.

[72] Song Y, Peng X, Porta A, et al. Calcium transporter 1 and epithelial calcium channel messenger ribonucleic acid are differentially regulated by 1,25 dihydroxyvitamin D3 in the intestine

and kidney of mice. Endocrinology. 2003;144(9):3885-94.

[73] Bianco SD, Peng JB, Takanaga H, et al. Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene. J Bone Miner Res. 2007;22(2):274-85.

[74] Glenney JR Jr, Glenney P. Comparison of Ca++-regulated events in the intestinal brush border. J Cell Biol. 1985;100(3):754-63.

[75] Ghijsen WE, De Jong MD, Van Os CH. ATP-dependent calcium transport and its correlation with Ca2+ -ATPase activity in basolateral plasma membranes of rat duodenum. Biochim Biophys Acta. 1982;689(2):327-36.

[76] Lee GS, Lee KY, Choi KC, et al. Phenotype of a calbindin-D9k gene knockout is compensated for by the induction of other calcium transporter genes in a mouse model. J Bone Miner Res. 2007;22(12):1968-78.

[77] Benn BS, Ajibade D, Porta A, et al. Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k. Endocrinology. 2008;149(6):3196-205.

[78] Fujita H, Sugimoto K, Inatomi S, et al. Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. Mol Biol Cell. 2008;19(5):1912-21.

[79] Karbach U. Paracellular calcium transport across the small intestine. J Nutr. 1992;122(3 Suppl):672-7.

[80] Peterlik M, Wasserman RH. Regulation by vitamin D of intestinal phosphate absorption. Horm Metab Res. 1980;12(5):216-9.

[81] Friedman PA, Gesek FA. Cellular calcium transport in renal epithelia:

**23**

*Vitamin D Metabolism*

regulation. Physiol Rev. 1995;75(3):429-71.

2005;146(11):4647-56.

[83] Wang L, Nancollas GH, Henneman ZJ, Klein E, Weiner S. Nanosized particles in bone and dissolution insensitivity of bone

mineral. Biointerphases. 2006;1(3):106-11.

*DOI: http://dx.doi.org/10.5772/intechopen.97180*

1,25-dihydroxyvitamin D3 synthesis in isolated chick renal mitochondria. The role of calcium as influenced by

inorganic phosphate and hydrogen-ion. J Clin Invest. 1975;55(2):299-304.

hydroxylase gene in normocalcemic rats.

[91] Robinson CJ, Spanos E, James MF, et al. Role of prolactin in vitamin D metabolism and calcium absorption during lactation in the rat. J Endocrinol.

[92] Wang Z, Schuetz EG, Xu Y, Thummel KE. Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. J Steroid Biochem Mol

functions of vitamin D. Pediatr Endocrinol Rev. 2010;8(2):103-7.

[94] Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol.

[95] Jones G. Assay of vitamins D2 and D3, and 25-hydroxyvitamins D2 and D3 in human plasma by high-performance liquid chromatography. Clin Chem.

[97] Dirks NF, Ackermans MT, Lips P, et al. The When, What & How of Measuring Vitamin D Metabolism in

[93] Weisman Y. Non-classic unexpected

[90] Shinki T, Ueno Y, DeLuca HF, Suda T. Calcitonin is a major regulator

for the expression of renal 25-hydroxyvitamin D3-1alpha-

Proc Natl Acad Sci U S A. 1999;96(14):8253-8.

1982;94(3):443-53.

Biol. 2013;136:54-8.

2009;19(2):73-8.

1978;24(2):287-98.

[96] Hollis BW. Editorial: The determination of circulating 25-hydroxyvitamin D: no easy task.

Clinical Medicine. Nutrients.

2018;10(4). pii: E482

J Clin Endocrinol Metab. 2004;89(7):3149-51.

[82] Yu X, Ibrahimi OA, Goetz R, et al. Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology.

[84] Peacock M. Calcium metabolism in health and disease. Clin J Am Soc Nephrol. 2010;5(Suppl 1):23-30.

[85] Robertson WG, Marshall RW. Calcium measurements in serum and plasma--total and ionized. CRC Crit Rev

Clin Lab Sci. 1979;11(3):271-304.

[86] Kim S, Yamazaki M, Zella LA, Shevde NK, Pike JW. Activation of receptor activator of NF-kappaB ligand

1,25-dihydroxyvitamin D3 is mediated through multiple long-range enhancers. Mol Cell Biol. 2006;26(17):6469-86.

[87] Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ.

Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and

1,25-Dihydroxyvitamin D3 regulates the expression of low-density lipoprotein

ligand families. Endocr Rev.

[88] Fretz JA, Zella LA, Kim S,

receptor-related protein 5 via deoxyribonucleic acid sequence elements located downstream of the start site of transcription. Mol Endocrinol. 2006;20(9):2215-30.

[89] Bikle DD, Murphy EW, Rasmussen H. The ionic control of

1999;20(3):345-57.

Shevde NK, Pike JW.

gene expression by

measurement, mechanisms, and

*Vitamin D Metabolism DOI: http://dx.doi.org/10.5772/intechopen.97180*

measurement, mechanisms, and regulation. Physiol Rev. 1995;75(3):429-71.

*Vitamin D*

1990;127(1):39-45.

monophosphate-dependent protein kinase in the 1,25-dihydroxy-vitamin D3-mediated rapid stimulation of intestinal calcium transport, (transcaltachia). Endocrinology.

and kidney of mice. Endocrinology.

[73] Bianco SD, Peng JB, Takanaga H, et al. Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel

Comparison of Ca++-regulated events in the intestinal brush border. J Cell Biol.

[75] Ghijsen WE, De Jong MD, Van Os CH. ATP-dependent calcium transport and its correlation with Ca2+ -ATPase activity in basolateral plasma membranes of rat duodenum. Biochim Biophys Acta. 1982;689(2):327-36.

[76] Lee GS, Lee KY, Choi KC, et al. Phenotype of a calbindin-D9k gene knockout is compensated for by the induction of other calcium transporter genes in a mouse model. J Bone Miner

[77] Benn BS, Ajibade D, Porta A, et al. Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-

[78] Fujita H, Sugimoto K, Inatomi S, et al. Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. Mol Biol Cell. 2008;19(5):1912-21.

[79] Karbach U. Paracellular calcium transport across the small intestine. J Nutr. 1992;122(3 Suppl):672-7.

[80] Peterlik M, Wasserman RH. Regulation by vitamin D of intestinal phosphate absorption. Horm Metab Res.

[81] Friedman PA, Gesek FA. Cellular calcium transport in renal epithelia:

1980;12(5):216-9.

Res. 2007;22(12):1968-78.

D9k. Endocrinology. 2008;149(6):3196-205.

2003;144(9):3885-94.

gene. J Bone Miner Res. 2007;22(2):274-85.

1985;100(3):754-63.

[74] Glenney JR Jr, Glenney P.

[67] Norman AW, Okamura WH, Hammond MW, et al. Comparison of 6-s-cis- and 6-s-trans-locked analogs of

1alpha,25-dihydroxyvitamin D3 indicates that the 6-s-cis conformation is preferred for rapid nongenomic biological responses and that neither 6-s-cis- nor 6-s-trans-locked analogs are

preferred for genomic biological responses. Mol Endocrinol. 1997;11(10):1518-31.

[68] Sequeira VB, Rybchyn MS, Tongkao-On W, et al. The role of the vitamin D receptor and ERp57 in photoprotection by 1α,25-

2012;26(4):574-82.

dihydroxyvitamin D3. Mol Endocrinol.

[69] Mizwicki MT, Norman AW. The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling. Sci Signal. 2009;2(75):re4.

[70] Nemere I, Farach-Carson MC, Rohe B, et al. Ribozyme knockdown functionally links a 1,25(OH)2D3 membrane binding protein

A. 2004;101(19):7392-7.

2004;18(11):2660-71.

[71] Huhtakangas JA, Olivera CJ,

vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha,25(OH)2-vitamin D3 in vivo and in vitro. Mol Endocrinol.

[72] Song Y, Peng X, Porta A, et al. Calcium transporter 1 and epithelial calcium channel messenger ribonucleic acid are differentially regulated by 1,25 dihydroxyvitamin D3 in the intestine

(1,25D3-MARRS) and phosphate uptake in intestinal cells. Proc Natl Acad Sci U S

Bishop JE, Zanello LP, Norman AW. The

**22**

[82] Yu X, Ibrahimi OA, Goetz R, et al. Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology. 2005;146(11):4647-56.

[83] Wang L, Nancollas GH, Henneman ZJ, Klein E, Weiner S. Nanosized particles in bone and dissolution insensitivity of bone mineral. Biointerphases. 2006;1(3):106-11.

[84] Peacock M. Calcium metabolism in health and disease. Clin J Am Soc Nephrol. 2010;5(Suppl 1):23-30.

[85] Robertson WG, Marshall RW. Calcium measurements in serum and plasma--total and ionized. CRC Crit Rev Clin Lab Sci. 1979;11(3):271-304.

[86] Kim S, Yamazaki M, Zella LA, Shevde NK, Pike JW. Activation of receptor activator of NF-kappaB ligand gene expression by 1,25-dihydroxyvitamin D3 is mediated through multiple long-range enhancers. Mol Cell Biol. 2006;26(17):6469-86.

[87] Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 1999;20(3):345-57.

[88] Fretz JA, Zella LA, Kim S, Shevde NK, Pike JW. 1,25-Dihydroxyvitamin D3 regulates the expression of low-density lipoprotein receptor-related protein 5 via deoxyribonucleic acid sequence elements located downstream of the start site of transcription. Mol Endocrinol. 2006;20(9):2215-30.

[89] Bikle DD, Murphy EW, Rasmussen H. The ionic control of 1,25-dihydroxyvitamin D3 synthesis in isolated chick renal mitochondria. The role of calcium as influenced by inorganic phosphate and hydrogen-ion. J Clin Invest. 1975;55(2):299-304.

[90] Shinki T, Ueno Y, DeLuca HF, Suda T. Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D3-1alphahydroxylase gene in normocalcemic rats. Proc Natl Acad Sci U S A. 1999;96(14):8253-8.

[91] Robinson CJ, Spanos E, James MF, et al. Role of prolactin in vitamin D metabolism and calcium absorption during lactation in the rat. J Endocrinol. 1982;94(3):443-53.

[92] Wang Z, Schuetz EG, Xu Y, Thummel KE. Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. J Steroid Biochem Mol Biol. 2013;136:54-8.

[93] Weisman Y. Non-classic unexpected functions of vitamin D. Pediatr Endocrinol Rev. 2010;8(2):103-7.

[94] Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73-8.

[95] Jones G. Assay of vitamins D2 and D3, and 25-hydroxyvitamins D2 and D3 in human plasma by high-performance liquid chromatography. Clin Chem. 1978;24(2):287-98.

[96] Hollis BW. Editorial: The determination of circulating 25-hydroxyvitamin D: no easy task. J Clin Endocrinol Metab. 2004;89(7):3149-51.

[97] Dirks NF, Ackermans MT, Lips P, et al. The When, What & How of Measuring Vitamin D Metabolism in Clinical Medicine. Nutrients. 2018;10(4). pii: E482

[98] Pearce SH, Cheetham TD. Diagnosis and management of vitamin D deficiency. BMJ. 2010;340:b5664.

[99] Heijboer AC, Blankenstein MA, Kema IP, Buijs MM. Accuracy of 6 routine 25-hydroxyvitamin D assays: influence of vitamin D binding protein concentration. Clin Chem. 2012;58(3):543-8.

[100] Elsenberg EHAM, Ten Boekel E, Huijgen H, Heijboer AC. Standardization of automated 25-hydroxyvitamin D assays: How successful is it? Clin Biochem. 2017;50(18):1126-1130.

[101] Le Goff C, Peeters S, Crine Y, Lukas P, Souberbielle JC, Cavalier E. Evaluation of the cross-reactivity of 25-hydroxyvitamin D2 on seven commercial immunoassays on native samples. Clin Chem Lab Med. 2012;50(11):2031-2.

[102] Carter GD, Jones JC, Shannon J, et al. 25-Hydroxyvitamin D assays: Potential interference from other circulating vitaminD metabolites. J Steroid Biochem Mol Biol. 2016;164:134-138.

[103] Saggese G, Vierucci F, Prodam F, et al. Vitamin D in pediatric age: consensus of the Italian Pediatric Society and the Italian Society of Preventive and Social Pediatrics, jointly with the Italian Federation of Pediatricians. Ital J Pediatr. 2018;44(1):51.

[104] Dong Y, Pollock N, Stallmann-Jorgensen IS, et al. Low 25-hydroxyvitamin D levels in adolescents: race, season, adiposity, physical activity, and fitness. Pediatrics. 2010;125(6):1104-11.

[105] Earthman CP, Beckman LM, Masodkar K, Sibley SD. The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications. Int J Obes (Lond). 2012;36(3):387-96.

[106] Bikle DD, Gee E, Halloran B, Kowalski MA, Ryzen E, Haddad JG. Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J Clin Endocrinol Metab. 1986; 63(4):954-9.

[107] Schwartz JB, Lai J, Lizaola B, et al. A comparison of measured and calculated free 25(OH) vitamin D levels in clinical populations. J Clin Endocrinol Metab. 2014;99(5):1631-7.

**25**

**Chapter 2**

**Abstract**

**1. Introduction**

Vitamin D Deficiency in Pregnant

*Neelakanta Kanike, Naveen Kannekanti and Jenny Camacho*

Vitamin-D is not only an essential element in bone health, but it is also a pro-hormone. Deficiency of vitamin D is the most common cause of rickets and is also known to increase the risk of respiratory distress syndrome, lower respiratory infections, food sensitivities, asthma, type I diabetes, autism and schizophrenia. Vitamin D deficiency limits the effective absorption of dietary calcium and phosphorus. Vitamin D status in newborns is entirely dependent on maternal supply during pregnancy. Low maternal vitamin D status during pregnancy is a major risk factor for rickets in infants. Rickets in children is caused by severe, chronic vitamin D deficiency with apparent skeletal abnormalities, but neonates with vitamin D insufficiency have no overt skeletal or calcium metabolism defects. Rickets was a global disease in the early twentieth century. It has nearly disappeared in developed countries after its causal pathway was understood and fortification of milk with the hormone vitamin D was introduced at the population level. Surprisingly, rickets is re-emerging per recent evidence. Vitamin D deficiency is prevalent in both developed and developing countries. The chapter will review the prevalence of vitamin D deficiency in pregnant women and newborn population and its adverse effects on pregnancy and infant's health. The chapter also describes evidence-based recommendations to prevent vitamin D deficiency in these vulnerable population.

**Keywords:** Vitamin D, deficiency, newborn, preterm, rickets, pregnancy

Vitamin D is a fat-soluble secosteroid. It is a prohormone that can be ingested or derived from body sterols by the photolytic activity of ultraviolet rays on human skin. Vitamin-D is not only an essential element in bone health, but it is also a pro-hormone that plays a well-recognized role in other organs of body. Vitamin D deficiency is a worldwide health issue that affects more than one billion children and adults globally [1]. Vitamin-D deficiency in neonates has been linked to higher risk of respiratory distress syndrome, lower respiratory infections, food sensitivities, asthma, type I diabetes, autism and schizophrenia [2–9]. Serum 25-hydroxycholecalciferol (25[OH]D) is the main circulating metabolite of vitamin D with a reported half-life of approximately three weeks [10]. It is the best estimator of human body vitamin D stores. During pregnancy it crosses the placenta through passive or facilitated transport according to a concentration gradient [11, 12]. Vitamin-D status in the fetus and newborn infant is largely determined by maternal vitamin-D status [11]. The main risk factor for vitamin-D deficiency in neonates

Women and Newborn

#### **Chapter 2**

*Vitamin D*

[98] Pearce SH, Cheetham TD. Diagnosis

25-hydroxyvitamin D concentrations: considerations and implications. Int J Obes (Lond). 2012;36(3):387-96.

[106] Bikle DD, Gee E, Halloran B, Kowalski MA, Ryzen E, Haddad JG. Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J Clin Endocrinol

[107] Schwartz JB, Lai J, Lizaola B, et al.

calculated free 25(OH) vitamin D levels in clinical populations. J Clin Endocrinol

A comparison of measured and

Metab. 1986; 63(4):954-9.

Metab. 2014;99(5):1631-7.

and management of vitamin D deficiency. BMJ. 2010;340:b5664.

concentration. Clin Chem.

Huijgen H, Heijboer AC. Standardization of automated 25-hydroxyvitamin D assays: How successful is it? Clin Biochem. 2017;50(18):1126-1130.

2012;50(11):2031-2.

2016;164:134-138.

2018;44(1):51.

2012;58(3):543-8.

[99] Heijboer AC, Blankenstein MA, Kema IP, Buijs MM. Accuracy of 6 routine 25-hydroxyvitamin D assays: influence of vitamin D binding protein

[100] Elsenberg EHAM, Ten Boekel E,

[101] Le Goff C, Peeters S, Crine Y, Lukas P, Souberbielle JC, Cavalier E. Evaluation of the cross-reactivity of 25-hydroxyvitamin D2 on seven commercial immunoassays on native samples. Clin Chem Lab Med.

[102] Carter GD, Jones JC, Shannon J, et al. 25-Hydroxyvitamin D assays: Potential interference from other circulating vitaminD metabolites. J Steroid Biochem Mol Biol.

[103] Saggese G, Vierucci F, Prodam F, et al. Vitamin D in pediatric age: consensus of the Italian Pediatric Society and the Italian Society of Preventive and Social Pediatrics, jointly

with the Italian Federation of Pediatricians. Ital J Pediatr.

Stallmann-Jorgensen IS, et al. Low 25-hydroxyvitamin D levels in adolescents: race, season, adiposity, physical activity, and fitness. Pediatrics.

[105] Earthman CP, Beckman LM, Masodkar K, Sibley SD. The link between obesity and low circulating

[104] Dong Y, Pollock N,

2010;125(6):1104-11.

**24**

## Vitamin D Deficiency in Pregnant Women and Newborn

*Neelakanta Kanike, Naveen Kannekanti and Jenny Camacho*

#### **Abstract**

Vitamin-D is not only an essential element in bone health, but it is also a pro-hormone. Deficiency of vitamin D is the most common cause of rickets and is also known to increase the risk of respiratory distress syndrome, lower respiratory infections, food sensitivities, asthma, type I diabetes, autism and schizophrenia. Vitamin D deficiency limits the effective absorption of dietary calcium and phosphorus. Vitamin D status in newborns is entirely dependent on maternal supply during pregnancy. Low maternal vitamin D status during pregnancy is a major risk factor for rickets in infants. Rickets in children is caused by severe, chronic vitamin D deficiency with apparent skeletal abnormalities, but neonates with vitamin D insufficiency have no overt skeletal or calcium metabolism defects. Rickets was a global disease in the early twentieth century. It has nearly disappeared in developed countries after its causal pathway was understood and fortification of milk with the hormone vitamin D was introduced at the population level. Surprisingly, rickets is re-emerging per recent evidence. Vitamin D deficiency is prevalent in both developed and developing countries. The chapter will review the prevalence of vitamin D deficiency in pregnant women and newborn population and its adverse effects on pregnancy and infant's health. The chapter also describes evidence-based recommendations to prevent vitamin D deficiency in these vulnerable population.

**Keywords:** Vitamin D, deficiency, newborn, preterm, rickets, pregnancy

#### **1. Introduction**

Vitamin D is a fat-soluble secosteroid. It is a prohormone that can be ingested or derived from body sterols by the photolytic activity of ultraviolet rays on human skin. Vitamin-D is not only an essential element in bone health, but it is also a pro-hormone that plays a well-recognized role in other organs of body. Vitamin D deficiency is a worldwide health issue that affects more than one billion children and adults globally [1]. Vitamin-D deficiency in neonates has been linked to higher risk of respiratory distress syndrome, lower respiratory infections, food sensitivities, asthma, type I diabetes, autism and schizophrenia [2–9]. Serum 25-hydroxycholecalciferol (25[OH]D) is the main circulating metabolite of vitamin D with a reported half-life of approximately three weeks [10]. It is the best estimator of human body vitamin D stores. During pregnancy it crosses the placenta through passive or facilitated transport according to a concentration gradient [11, 12]. Vitamin-D status in the fetus and newborn infant is largely determined by maternal vitamin-D status [11]. The main risk factor for vitamin-D deficiency in neonates

is maternal vitamin-D deficiency [13]. Rickets was a global problem in the early 20th century. It virtually disappeared in developed countries after its causal pathway was identified and fortification of milk with vitamin-D was implemented at population level [14]. Recent reports have suggested that rickets is re-emerging [15, 16] and vitamin-D deficiency is widespread in developed and developing countries [15, 17–21]. Globally, vitamin-D deficiency at birth is prevalent and in general reflects deficient maternal vitamin-D status [10, 22–24].

#### **2. Vitamin D metabolism and biological functions**

Vitamin D is unique among vitamins because it can be made in the skin from sunlight exposure. Vitamin D has two forms: Ergocalciferol (D2) and Cholecalciferol (D3). D2 is produced from ultraviolet irradiation of the yeast sterol ergosterol and is naturally found in sun-exposed mushrooms. D3 is synthesized in the skin from the cholesterol precursor 7-dehydrocholesterol which is naturally present in the skin or obtained from lanolin [25]. Vitamin D (in the form of D2, or D3, or both) that is ingested is assimilated into chylomicrons, which are absorbed into the lymphatic system and enter the venous blood. Vitamin D that comes from the skin or diet is biologically inert and needs its first hydroxylation in the liver by the vitamin D-25-hydroxylase to 25[OH]D [25, 26]. 25[OH]D undergoes a second hydroxylation in the kidneys by the 25[OH]D-1α-hydroxylase to form the biologically active form of vitamin D 1,25[OH]2D (3, 8). 1,25[OH]2D interacts with its vitamin D nuclear receptor, which is present in the small intestine, kidneys, and other tissues [25, 26].

1,25[OH]2D plays a main physiological role in bone hemostasis. It stimulates intestinal calcium absorption [27]. Without vitamin D, only 10 to 15% of dietary calcium and about 60% of phosphorus are absorbed. Vitamin D sufficiency enhances calcium and phosphorus absorption by 30–40% and 80%, respectively [25, 28]. 1,25[OH]2D interacts with its vitamin D receptor in the osteoblast to stimulate the expression of receptor activator of nuclear factor κB ligand; this, in turn, interacts with receptor activator of nuclear factor κB to induce immature monocytes to become mature osteoclasts, which dissolve the matrix and mobilize calcium and other minerals from the skeleton. In the kidney, 1,25[OH]2D stimulates calcium reabsorption from the glomerular filtrate [25, 29].

The strong correlation between maternal and infant 25[OH]D levels offers further evidence that newborn 25[OH]D levels are dependent on maternal plasma 25[OH]D levels [12, 30, 31]. There is no clear consensus on the cut off levels of serum 25[OH]D levels to define vitamin deficiency. The US Endocrine Society has categorized vitamin D deficiency as 25[OH]D < 20 ng/mL, vitamin D insufficiency as levels 21–30 ng/mL, sufficiency as levels greater than 30 ng/mL, and toxicity as vitamin D levels more than 150 ng/mL [32]. The American Academy of Pediatrics (AAP) and Institute of Medicine define vitamin D deficiency as serum 25[OH] D < 15 ng/mL, mild to moderate deficiency as 5–15 ng/mL, severe deficiency as levels less than 5 ng/mL, and insufficiency as 16–20 ng/mL. They define sufficiency as levels between 21 and 100 ng/mL, excess as 101–149 ng/mL, and intoxication as levels more than 150 ng/mL [33]. The Kidney Disease Outcome Quality Initiative supports the AAP in defining vitamin D deficiency as levels <15 ng/mL. However, it defines insufficiency as levels between 16 and 30 ng/mL and sufficiency as levels of more than 30 ng/mL. An expert committee of the US Food and Nutrition Board (FNB) at the National Academies of Sciences, Engineering, and Medicine (NASEM) concluded that people are at risk of vitamin D deficiency at serum 25[OH]D concentrations less than 12 ng/mL. The same cutoffs were used for both pregnant

**27**

25nmol/L [37].

**3.2 Developing countries**

*Vitamin D Deficiency in Pregnant Women and Newborn DOI: http://dx.doi.org/10.5772/intechopen.98454*

**3.1 Developed countries**

2003 and 2004 and 2011–2014 [34].

definition of vitamin-D sufficiency varies by age [16].

**3. Prevalence of vitamin D deficiency in pregnant women**

maternal body mass index of 35 (aOR: 2.78 [95% CI: 1.18–6.55]) [31].

women and neonates, because experts contend that there is no reason to think the

An US survey from National Health and Nutrition Examination Survey (NHANES) 2011–2014 on serum 25[OH]D levels found that 5.7% women had vitamin D deficiency (<12 ng/ml) and 17.8% women had vitamin D insufficiency (12–20 ng/mL). Rates of deficiency and insufficiency were 7.6% and 23.8% respectively in adults aged 20–39 years. Rates of deficiency varied by race and ethnicity: 17.5% of non-Hispanic Blacks, 7.6% of non-Hispanic Asians, 5.9% of Hispanics, and 2.1% of non-Hispanic White people were at risk of vitamin D deficiency respectively. Vitamin D status in the United States remained stable in the decade between

Boston's cross-sectional study from 2005 to 2007 reported vitamin-D deficiency (25[OH]D < 20 ng/mL) in 35.8% of the mothers and 58% of the neonates, severe deficiency (25[OH]D < 15 ng/mL) in 23.1% of the mothers and 38.0% of the neonates. Risk factors for neonatal vitamin-D deficiency included maternal deficiency (adjusted odds ratio [aOR]: 5.28 [95% CI: 2.90–9.62]), winter birth (aOR: 3.86 [95% CI: 1.74–8.55]), African-American (AA) race (aOR: 3.36 [95% CI: 1.37–8.25]), and

A Canadian study found a prevalence of 25% vitamin D insufficiency (defined as serum 25-[OH]D < 40 nmol/L) in women aged 18–35 years during the winter season [17]. Vitamin D deficiency is also common in Europe and the Middle East. Vitamin D deficiency defined as serum 25[OH]D < 50nmol/L or 20ng/mL, occurs in 6–33% of the population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and 30–90% in the Middle East countries. Severe deficiency (serum 25(OH)D < 30nmol/L or 12ng/mL) is found in >10% of Europeans [35]. Vitamin D deficiency is usually is more prevalent in immigrants from non-Western countries, compared with native European people [36]. This is even worse in pregnant non-Western immigrants, who displayed mean serum 25(OH)D levels around

The major proportion of vitamin D is produced endogenously with skin exposure of the skin to sunlight. In tropical areas like India, Africa and middle east, where there is abundant overhead sun for most or all of the year, deficiency of vitamin D is unexpected. However, despite stable and sufficient sun exposure in countries across equator, high prevalence of vitamin D deficiency in pregnancy ranging 26–95% in such areas was reported [38]. In Africa, Asia and the Middle East, women have been always regarded as "high risk" for vitamin D deficiency [39, 40]. In 2009, the International Osteoporosis Foundation reported that vitamin D deficiency was seen in 84% of pregnant women and 96% of infants in Asia [41]. In India, 50–90% of the population suffers from vitamin D deficiency due to inadequate exposure to sunlight and a lower dietary intake [42–44]. A recent study from northern India reported the prevalence of vitamin D deficiency in 85.5% of mothers and 74% of infants [45]. Vitamin D deficiency, defined as <50 nmol/L of 25[OH]D and severe vitamin D deficiency defined as <30 nmol/L of 25[OH]D was reported in 34% and 18% of the population respectively in African countries [46].

women and neonates, because experts contend that there is no reason to think the definition of vitamin-D sufficiency varies by age [16].

#### **3. Prevalence of vitamin D deficiency in pregnant women**

#### **3.1 Developed countries**

*Vitamin D*

maternal vitamin-D status [10, 22–24].

other tissues [25, 26].

**2. Vitamin D metabolism and biological functions**

calcium reabsorption from the glomerular filtrate [25, 29].

is maternal vitamin-D deficiency [13]. Rickets was a global problem in the early 20th century. It virtually disappeared in developed countries after its causal pathway was identified and fortification of milk with vitamin-D was implemented at population level [14]. Recent reports have suggested that rickets is re-emerging [15, 16] and vitamin-D deficiency is widespread in developed and developing countries [15, 17–21]. Globally, vitamin-D deficiency at birth is prevalent and in general reflects deficient

Vitamin D is unique among vitamins because it can be made in the skin from sunlight exposure. Vitamin D has two forms: Ergocalciferol (D2) and

Cholecalciferol (D3). D2 is produced from ultraviolet irradiation of the yeast sterol ergosterol and is naturally found in sun-exposed mushrooms. D3 is synthesized in the skin from the cholesterol precursor 7-dehydrocholesterol which is naturally present in the skin or obtained from lanolin [25]. Vitamin D (in the form of D2, or D3, or both) that is ingested is assimilated into chylomicrons, which are absorbed into the lymphatic system and enter the venous blood. Vitamin D that comes from the skin or diet is biologically inert and needs its first hydroxylation in the liver by the vitamin D-25-hydroxylase to 25[OH]D [25, 26]. 25[OH]D undergoes a second hydroxylation in the kidneys by the 25[OH]D-1α-hydroxylase to form the biologically active form of vitamin D 1,25[OH]2D (3, 8). 1,25[OH]2D interacts with its vitamin D nuclear receptor, which is present in the small intestine, kidneys, and

1,25[OH]2D plays a main physiological role in bone hemostasis. It stimulates intestinal calcium absorption [27]. Without vitamin D, only 10 to 15% of dietary calcium and about 60% of phosphorus are absorbed. Vitamin D sufficiency enhances calcium and phosphorus absorption by 30–40% and 80%, respectively [25, 28]. 1,25[OH]2D interacts with its vitamin D receptor in the osteoblast to stimulate the expression of receptor activator of nuclear factor κB ligand; this, in turn, interacts with receptor activator of nuclear factor κB to induce immature monocytes to become mature osteoclasts, which dissolve the matrix and mobilize calcium and other minerals from the skeleton. In the kidney, 1,25[OH]2D stimulates

The strong correlation between maternal and infant 25[OH]D levels offers further evidence that newborn 25[OH]D levels are dependent on maternal plasma 25[OH]D levels [12, 30, 31]. There is no clear consensus on the cut off levels of serum 25[OH]D levels to define vitamin deficiency. The US Endocrine Society has categorized vitamin D deficiency as 25[OH]D < 20 ng/mL, vitamin D insufficiency as levels 21–30 ng/mL, sufficiency as levels greater than 30 ng/mL, and toxicity as vitamin D levels more than 150 ng/mL [32]. The American Academy of Pediatrics (AAP) and Institute of Medicine define vitamin D deficiency as serum 25[OH] D < 15 ng/mL, mild to moderate deficiency as 5–15 ng/mL, severe deficiency as levels less than 5 ng/mL, and insufficiency as 16–20 ng/mL. They define sufficiency as levels between 21 and 100 ng/mL, excess as 101–149 ng/mL, and intoxication as levels more than 150 ng/mL [33]. The Kidney Disease Outcome Quality Initiative supports the AAP in defining vitamin D deficiency as levels <15 ng/mL. However, it defines insufficiency as levels between 16 and 30 ng/mL and sufficiency as levels of more than 30 ng/mL. An expert committee of the US Food and Nutrition Board (FNB) at the National Academies of Sciences, Engineering, and Medicine (NASEM)

concluded that people are at risk of vitamin D deficiency at serum 25[OH]D concentrations less than 12 ng/mL. The same cutoffs were used for both pregnant

**26**

An US survey from National Health and Nutrition Examination Survey (NHANES) 2011–2014 on serum 25[OH]D levels found that 5.7% women had vitamin D deficiency (<12 ng/ml) and 17.8% women had vitamin D insufficiency (12–20 ng/mL). Rates of deficiency and insufficiency were 7.6% and 23.8% respectively in adults aged 20–39 years. Rates of deficiency varied by race and ethnicity: 17.5% of non-Hispanic Blacks, 7.6% of non-Hispanic Asians, 5.9% of Hispanics, and 2.1% of non-Hispanic White people were at risk of vitamin D deficiency respectively. Vitamin D status in the United States remained stable in the decade between 2003 and 2004 and 2011–2014 [34].

Boston's cross-sectional study from 2005 to 2007 reported vitamin-D deficiency (25[OH]D < 20 ng/mL) in 35.8% of the mothers and 58% of the neonates, severe deficiency (25[OH]D < 15 ng/mL) in 23.1% of the mothers and 38.0% of the neonates. Risk factors for neonatal vitamin-D deficiency included maternal deficiency (adjusted odds ratio [aOR]: 5.28 [95% CI: 2.90–9.62]), winter birth (aOR: 3.86 [95% CI: 1.74–8.55]), African-American (AA) race (aOR: 3.36 [95% CI: 1.37–8.25]), and maternal body mass index of 35 (aOR: 2.78 [95% CI: 1.18–6.55]) [31].

A Canadian study found a prevalence of 25% vitamin D insufficiency (defined as serum 25-[OH]D < 40 nmol/L) in women aged 18–35 years during the winter season [17]. Vitamin D deficiency is also common in Europe and the Middle East. Vitamin D deficiency defined as serum 25[OH]D < 50nmol/L or 20ng/mL, occurs in 6–33% of the population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and 30–90% in the Middle East countries. Severe deficiency (serum 25(OH)D < 30nmol/L or 12ng/mL) is found in >10% of Europeans [35]. Vitamin D deficiency is usually is more prevalent in immigrants from non-Western countries, compared with native European people [36]. This is even worse in pregnant non-Western immigrants, who displayed mean serum 25(OH)D levels around 25nmol/L [37].

#### **3.2 Developing countries**

The major proportion of vitamin D is produced endogenously with skin exposure of the skin to sunlight. In tropical areas like India, Africa and middle east, where there is abundant overhead sun for most or all of the year, deficiency of vitamin D is unexpected. However, despite stable and sufficient sun exposure in countries across equator, high prevalence of vitamin D deficiency in pregnancy ranging 26–95% in such areas was reported [38]. In Africa, Asia and the Middle East, women have been always regarded as "high risk" for vitamin D deficiency [39, 40]. In 2009, the International Osteoporosis Foundation reported that vitamin D deficiency was seen in 84% of pregnant women and 96% of infants in Asia [41]. In India, 50–90% of the population suffers from vitamin D deficiency due to inadequate exposure to sunlight and a lower dietary intake [42–44]. A recent study from northern India reported the prevalence of vitamin D deficiency in 85.5% of mothers and 74% of infants [45]. Vitamin D deficiency, defined as <50 nmol/L of 25[OH]D and severe vitamin D deficiency defined as <30 nmol/L of 25[OH]D was reported in 34% and 18% of the population respectively in African countries [46].

Vitamin D deficiency is even worse in mainland China with deficiency seen in 72% and severe deficiency seen in 37% of pregnant women [47].

#### **4. Effects of vitamin D deficiency on pregnancy**

Despite the wide intake of prenatal vitamins, Vitamin D deficiency in pregnancy is still common worldwide. The adverse outcomes of pregnancy secondary to vitamin D deficiency include miscarriages, preeclampsia, intrauterine growth restriction (IUGR), increased risk for gestational diabetes, preterm birth and low birth weight infants [48–50]. Vitamin D deficiency in pregnant women may affect fetal growth, tooth enamel formation and bone ossification [13]. Decreased vitamin D levels in general is associated with increased mortality and vitamin D supplementation reduces mortality [51]. The reasons behind increased mortality include diabetes mellitus, cardiovascular disease and cancer [52]. Vitamin D deficiency has been associated with several autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Hashimoto Thyroiditis (HT), and multiple sclerosis (MS). Autoimmune diseases are more commonly seen in females than males. Pregnant women with these autoimmune disorders are at increased risk for poor pregnancy outcomes [48, 53].

Animal studies showed that vitamin D deficiency causes placental inflammation which leads to placental insufficiency and potentially fetal IUGR [53]. In both pregnancy and lactation it is important to have adequate vitamin D levels to avoid disturbances in bone and mineral metabolism [54]. The fetal and neonatal status of vitamin D is entirely dependent on the mother's vitamin D levels. This confirms the correlation of mother and cord blood 25[OH]D concentrations. While 25[OH] D crosses the placenta, 1,25[OH]2D is produced by the fetal kidneys [54]. Research regarding the exact physiological role of vitamin D in pregnancy and lactation is ongoing. There is convincing data that vitamin D is important for the immunomodulation of the maternal-fetal interface [54–58]. Vitamin D is also crucial for the prevention of pre-eclampsia by stabilizing the endothelium through non-genomic mechanisms [54]. Other functions of vitamin D may include stimulation of sex hormone secretion, implantation/placentation and respiratory epithelium maturation. Vitamin D may also induce epigenetic changes in expressing vitamin D receptors and enzymes involved in vit D metabolism throughout the male and female reproductive tracts [54–58].

#### **5. Etiology of vitamin D deficiency in pregnant women**

Vitamin D deficiency is prevalent worldwide in pregnant women and infants. In pregnancy, maternal vitamin D physiology is altered to facilitate the transfer of calcium to the fetus. In pregnancy there is a significant increase in 1,25[OH]2 D concentrations with a two-fold increase in the first trimester followed by a 2–3-fold increase during the second and third trimesters of pregnancy. Then there is a rapid decrease after delivery. PTH-related peptide may also regulate serum 1,25[OH]2D concentrations in pregnancy. 1,25[OH]2D synthesis is dependent up the levels of 25[OH]D. There is a positive correlation between serum 1,25[OH]2D and 25[OH] D concentrations and it is stronger in pregnant women compared to non-pregnant women [54].

Eating foods fortified with vitamin D as well as adequate exposure to sunlight are needed for upholding a normal vitamin D status. The most common reasons for vitamin D deficiency are low sun exposure, decreased vitamin D intake, obesity,

**29**

*Vitamin D Deficiency in Pregnant Women and Newborn DOI: http://dx.doi.org/10.5772/intechopen.98454*

antenatal care programs in developing countries like India [59].

ulcerative colitis and Crohn's disease [65].

and calcium is truncated [68].

**6. Prevalence of vitamin D deficiency in newborn**

and low socio-economic conditions. Various factors influence vitamin D synthesis from sunlight, such as latitude, pigmentation, and area of skin exposed. Many prevalent social and cultural practices in Asia and middle east that prevent the adequate exposure of young women and adolescent girls to sunlight contribute to vitamin D deficiency [59]. Increasing urbanization resulting in greater pollution and decreased time spent outdoors coupled with greater skin pigmentation contribute to vitamin D deficiency [60]. When women in these circumstances become pregnant with already low serum 25 [OH]D levels, this contributes to vitamin D deficiency or insufficiency in their offspring. These children at increased risk for developing rickets [49]. Furthermore, vitamin D supplementation is not part of

Diets low in vitamin D are more common in people who have milk allergy or lactose intolerance and those who consume an ovo-vegetarian or vegan diet. Women who are homebound, have occupations that limit sun exposure, or who wear long dresses, robes, or head coverings for religious reasons are at risk for vitamin D deficiency due to limited exposure to sunlight [61]. The use of sunscreen also limits vitamin D synthesis from sunlight. Obese women have lower vitamin D levels than nonobese individuals. The skin's capacity to produce vitamin D is not affected by obesity. In fact, thick subcutaneous fat sequesters more of vitamin D [62, 63]. Serum levels transiently increase following weight loss possibly due to the release of vitamin D in the circulation. This was noted in obese patients after roux-en-y gastric bypass surgery as well as patients with non-surgical weight loss. However, 1 year after a Roux-en-y gastric bypass surgery, vitamin D levels returned to baseline values [64]. Finally, since vitamin D is fat soluble, its absorption is poor in individuals with fat malabsorption disorders like celiac disease, cystic fibrosis,

Due to the bone deposition that mostly occurs in the latter half of the pregnancy,

vitamin D requirements for the fetus are higher at this time frame [66]. In early pregnancy the plasma levels of 1,25(OH)2D increase and peak in the third trimester. It is estimated that the fetus accumulates 2–3 mg/day of calcium in the skeleton in the first trimester. This calcium accumulation doubles in the third trimester [67]. When infants are born prematurely, the time required for this transfer of Vitamin D

Saraf and et al. conducted a global summary and systematic review of maternal and newborn vitamin D status by looking at studies published between 1959 and 2014. They found that 75% of newborns had vitamin D deficiency (defined as 25[OH]D level < 50 nmol/L) and that severe vitamin D deficiency (defined as 25[OH]D level < 25 nmol/L) occurred in 29% of newborns. In this summary, the average newborn 25[OH]D levels in nmol/L by region is as follows: 35–77 (Americans), 20–50 (European), 5–50 (Mediterranean), 20–22 (South-East Asia), 32–67 (Western Pacific) and 27–35 (African). They also found wide variability in 25[OH]D levels within in each defined region [24]. Both this study and another systemic review by Hilger and colleagues found that the average 25[OH]D levels in the general populations in North America were higher compared to Europe and the Middle East [69]. Furthermore, two other reviews found that vitamin D deficiency and severe vitamin D deficiency were more common in South-East Asia and the Eastern Mediterranean regions for newborns [41, 70]. Racial disparity in serum 25[OH]D levels has been well documented in several studies. AA preterm infants and their mothers have lower serum 25[OH]D levels compared to white infants [71–73].

*Vitamin D Deficiency in Pregnant Women and Newborn DOI: http://dx.doi.org/10.5772/intechopen.98454*

*Vitamin D*

Vitamin D deficiency is even worse in mainland China with deficiency seen in 72%

Despite the wide intake of prenatal vitamins, Vitamin D deficiency in pregnancy is still common worldwide. The adverse outcomes of pregnancy secondary to vitamin D deficiency include miscarriages, preeclampsia, intrauterine growth restriction (IUGR), increased risk for gestational diabetes, preterm birth and low birth weight infants [48–50]. Vitamin D deficiency in pregnant women may affect fetal growth, tooth enamel formation and bone ossification [13]. Decreased vitamin D levels in general is associated with increased mortality and vitamin D supplementation reduces mortality [51]. The reasons behind increased mortality include diabetes mellitus, cardiovascular disease and cancer [52]. Vitamin D deficiency has been associated with several autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Hashimoto Thyroiditis (HT), and multiple sclerosis (MS). Autoimmune diseases are more commonly seen in females than males. Pregnant women with these autoimmune disorders are at increased risk for poor pregnancy outcomes [48, 53]. Animal studies showed that vitamin D deficiency causes placental inflammation which leads to placental insufficiency and potentially fetal IUGR [53]. In both pregnancy and lactation it is important to have adequate vitamin D levels to avoid disturbances in bone and mineral metabolism [54]. The fetal and neonatal status of vitamin D is entirely dependent on the mother's vitamin D levels. This confirms the correlation of mother and cord blood 25[OH]D concentrations. While 25[OH] D crosses the placenta, 1,25[OH]2D is produced by the fetal kidneys [54]. Research regarding the exact physiological role of vitamin D in pregnancy and lactation is ongoing. There is convincing data that vitamin D is important for the immunomodulation of the maternal-fetal interface [54–58]. Vitamin D is also crucial for the prevention of pre-eclampsia by stabilizing the endothelium through non-genomic mechanisms [54]. Other functions of vitamin D may include stimulation of sex hormone secretion, implantation/placentation and respiratory epithelium maturation. Vitamin D may also induce epigenetic changes in expressing vitamin D receptors and enzymes involved in vit D metabolism throughout the male and female repro-

and severe deficiency seen in 37% of pregnant women [47].

**4. Effects of vitamin D deficiency on pregnancy**

**28**

women [54].

ductive tracts [54–58].

**5. Etiology of vitamin D deficiency in pregnant women**

Vitamin D deficiency is prevalent worldwide in pregnant women and infants. In pregnancy, maternal vitamin D physiology is altered to facilitate the transfer of calcium to the fetus. In pregnancy there is a significant increase in 1,25[OH]2 D concentrations with a two-fold increase in the first trimester followed by a 2–3-fold increase during the second and third trimesters of pregnancy. Then there is a rapid decrease after delivery. PTH-related peptide may also regulate serum 1,25[OH]2D concentrations in pregnancy. 1,25[OH]2D synthesis is dependent up the levels of 25[OH]D. There is a positive correlation between serum 1,25[OH]2D and 25[OH] D concentrations and it is stronger in pregnant women compared to non-pregnant

Eating foods fortified with vitamin D as well as adequate exposure to sunlight are needed for upholding a normal vitamin D status. The most common reasons for vitamin D deficiency are low sun exposure, decreased vitamin D intake, obesity,

and low socio-economic conditions. Various factors influence vitamin D synthesis from sunlight, such as latitude, pigmentation, and area of skin exposed. Many prevalent social and cultural practices in Asia and middle east that prevent the adequate exposure of young women and adolescent girls to sunlight contribute to vitamin D deficiency [59]. Increasing urbanization resulting in greater pollution and decreased time spent outdoors coupled with greater skin pigmentation contribute to vitamin D deficiency [60]. When women in these circumstances become pregnant with already low serum 25 [OH]D levels, this contributes to vitamin D deficiency or insufficiency in their offspring. These children at increased risk for developing rickets [49]. Furthermore, vitamin D supplementation is not part of antenatal care programs in developing countries like India [59].

Diets low in vitamin D are more common in people who have milk allergy or lactose intolerance and those who consume an ovo-vegetarian or vegan diet. Women who are homebound, have occupations that limit sun exposure, or who wear long dresses, robes, or head coverings for religious reasons are at risk for vitamin D deficiency due to limited exposure to sunlight [61]. The use of sunscreen also limits vitamin D synthesis from sunlight. Obese women have lower vitamin D levels than nonobese individuals. The skin's capacity to produce vitamin D is not affected by obesity. In fact, thick subcutaneous fat sequesters more of vitamin D [62, 63]. Serum levels transiently increase following weight loss possibly due to the release of vitamin D in the circulation. This was noted in obese patients after roux-en-y gastric bypass surgery as well as patients with non-surgical weight loss. However, 1 year after a Roux-en-y gastric bypass surgery, vitamin D levels returned to baseline values [64]. Finally, since vitamin D is fat soluble, its absorption is poor in individuals with fat malabsorption disorders like celiac disease, cystic fibrosis, ulcerative colitis and Crohn's disease [65].

#### **6. Prevalence of vitamin D deficiency in newborn**

Due to the bone deposition that mostly occurs in the latter half of the pregnancy, vitamin D requirements for the fetus are higher at this time frame [66]. In early pregnancy the plasma levels of 1,25(OH)2D increase and peak in the third trimester. It is estimated that the fetus accumulates 2–3 mg/day of calcium in the skeleton in the first trimester. This calcium accumulation doubles in the third trimester [67]. When infants are born prematurely, the time required for this transfer of Vitamin D and calcium is truncated [68].

Saraf and et al. conducted a global summary and systematic review of maternal and newborn vitamin D status by looking at studies published between 1959 and 2014. They found that 75% of newborns had vitamin D deficiency (defined as 25[OH]D level < 50 nmol/L) and that severe vitamin D deficiency (defined as 25[OH]D level < 25 nmol/L) occurred in 29% of newborns. In this summary, the average newborn 25[OH]D levels in nmol/L by region is as follows: 35–77 (Americans), 20–50 (European), 5–50 (Mediterranean), 20–22 (South-East Asia), 32–67 (Western Pacific) and 27–35 (African). They also found wide variability in 25[OH]D levels within in each defined region [24]. Both this study and another systemic review by Hilger and colleagues found that the average 25[OH]D levels in the general populations in North America were higher compared to Europe and the Middle East [69]. Furthermore, two other reviews found that vitamin D deficiency and severe vitamin D deficiency were more common in South-East Asia and the Eastern Mediterranean regions for newborns [41, 70]. Racial disparity in serum 25[OH]D levels has been well documented in several studies. AA preterm infants and their mothers have lower serum 25[OH]D levels compared to white infants [71–73].

Seto and colleagues measured cord blood 25 [OH]D levels in 276 AA term infants and 162 term white infants and found that AA infants had a 3.6 greater adjusted odds of vitamin D deficiency [74].

Currently, there continues to be emerging information on the distribution of 25[OH]D levels in preterm neonates. A few studies have documented 25[OH]D levels from neonates at birth with sample sizes ranging from 8 to 278 neonates [2, 75–80] with mean 25[OH]D levels ranging from ~6.5 ng/mL among preterm neonates in the United Arab Emirates [78] to 26.8 ng/mL preterm neonates in Canada [10]. A recent study on 596 preterm infants from Ohio, USA reported median 25[OH]D level of 18.5 ng/mL for infants born at 34–36 weeks and 18.6 ng/mL for infants born <32 weeks [81].

The levels of 25[OH]D between the mother and the fetus are positively correlated [68, 81, 82]. Kassai et al. found that mothers who gave birth to preterm neonates had significantly lower mean 25[OH]D blood levels compared to those mothers who gave birth at term. Also, preterm neonates had significantly lower 25[OH]D levels compared to term neonates [83]. A study by Burris et al. measured umbilical cord plasma levels of 25[OH]D in 471 infants born at <37 weeks. They found that babies born at <32 weeks are at increased risk for vitamin D deficiency (25[OH]D levels <20 ng/dL) compared to infants born between 32 and 37 weeks [79]. Monagni et al. studied 120 mother infant dyads at three children's hospitals in Ohio where neonates were delivered at <32 weeks. They not only found that low serum concentrations of 25[OH]D (defined as <50 nmol/L) was common in preterm neonates at admission (64%), but they also found that maternal 25[OH]D levels were lower in infants born at <28 weeks compared to those that were born between 28 and 32 weeks' gestation. Serum 25[OH]D concentrations in preterm infants directly correlated with maternal vitamin D status at the time of delivery. Low 25[OH]D levels were noted at either 36 weeks post-menstrual age (PMA) or at discharge in 40% of infants <28 weeks and 30% of infants between 28 and 32 weeks PMA. Even though infants received vitamin D supplementation from various sources and intake progressively increased during their hospitalization, only 60% received 400 IU vitamin D daily by 36 weeks PMA or discharge [68].

In contrast to the above studies, a Canadian study and an US study did not show any significant difference in vitamin-D status between term and preterm neonates [10, 81]. A study of 3731 term infants in Jordan revealed that 94% had vitamin D deficiency defined as 25[OH]D level < 50 nmol/L. Shahraki et al. found that 25[OH]D levels in preterm neonates were not significantly lower than term neonates. Over 50% of both the term and preterm infants in this study had vitamin D insufficiency and about 25% had vitamin D deficiency [82]. In a cohort born in Cleveland area in US (latitude 410 N), Kanike et al. reported a remarkably high proportion of vitamin-D deficiency and insufficiency among neonates at birth, 31% and 49% respectively. Notably, they noted low stores of vitamin D despite 75% of women reporting regular multivitamin intake during pregnancy. Vitamin D deficiency was found to be more common in AA neonates (63%) than Caucasian (27%) neonates [81]. Bodnar et.al studied 400 mother–infant pairs in Pittsburgh. They showed that nearly 50% of AA neonates and 10% of white neonates, had serum 25[OH]D levels at birth less than 15 ng/mL despite adequate compliance with a 400 IU daily vitamin-D intake by 90% of their mothers [22]. A prolonged winter season with limited sun exposure in Cleveland might be a contributing factor to the vitamin-D deficiency found in this population. There has been no significant improvement in the vitamin-D status among neonates born to AA women in the last 3 decades in Cleveland area [12].

**31**

birth [96].

**for vitamin D deficiency**

*Vitamin D Deficiency in Pregnant Women and Newborn DOI: http://dx.doi.org/10.5772/intechopen.98454*

**7. Consequences of vitamin D deficiency in children**

and was associated with increased severity of sepsis and mortality [87].

children born with low serum 25[OH]D concentrations [94].

Vitamin D deficiency prevents effective absorption of dietary calcium and phosphorus. Vitamin D stores in newborn are completely dependent on vitamin D supply from the mother [12]. Not surprisingly, poor maternal vitamin D status during pregnancy is a major risk factor for infant rickets [13, 88, 89]. Severe chronic vitamin D deficiency leads to overt skeletal abnormalities in children like rickets [90, 91]. However, neonates who are vitamin-D insufficient have no apparent skeletal or calcium metabolism abnormalities [16]. In developing countries rickets has been ranked among the five most prevalent diseases in children [92]. Poorer outcomes during pregnancy, at birth and during infancy are associated with lower serum 25[OH]D levels [24, 93]. Reduced bone mass at 9 years of age was seen in

There is conflicting data about role of vitamin D and neurodevelopmental outcomes. A meta-analysis by Tous and colleauges found that infants born to mothers with vitamin D insufficiency had lower scores in both mental and language development [95]. In contrast, Wang et al. found that vitamin D deficiency was not associated with neurodevelopment in infancy [84]. A prospective cohort study by McCarthy et al. found no association between antenatal 25[OH]D levels and neurodevelopmental outcomes at 5 years. Tous et al. found that maternal vitamin D deficiency is associated with lower birth weights, smaller head circumference, increased risk for small for gestational age (SGA) status, and preterm birth. Maternal vitamin D insufficiency was associated with increased risk for infants with SGA status and preterm birth [95]. Seto and colleagues found that black infants with vitamin D deficiency had 2.4 greater adjusted odds for SGA status at birth. The association between SGA and vitamin D deficiency was not demonstrated in white infants [74]. Furthermore, a systematic review by Pligt et al. found the maternal vitamin D deficiency was associated with low birth weight, SGA status at birth, stunting of growth immediately after delivery, and preterm

**8. Recommended dietary intake in pregnant women and Newborn at risk** 

As per the US federal government's 2020–2025 guidelines, fortified foods and dietary supplements are beneficial when it is impossible to meet needs for one or more nutrients during certain life stages such as pregnancy. Milk, many ready-to-eat cereals, and some brands of yogurt, orange juice and margarines are fortified with vitamin D. Trout, tuna, salmon, and mackerel are fatty fish with a high content of vitamin D. One tablespoon of cod liver oil has 1360 IU of vitamin D. Cheese, beef liver and egg yolks naturally contain small amounts of vitamin D. The United States

Vitamin-D deficiency is the most common cause of rickets and also increases the risk of respiratory distress syndrome, lower respiratory infections, food sensitivities, asthma, type I diabetes, autism and schizophrenia [2, 3, 6, 8, 15]. Vitamin D deficiency in pregnancy impairs fetal lung development partially through suppressing type II pneumocyte differentiation increasing the risk of respiratory distress syndrome in the newborn period [84]. Furthermore, studies have shown that early onset sepsis and late onset sepsis occurs more frequently in term infants with vitamin D deficiency [85–87]. To highlight, one study by Singh and Chaudari found that vitamin D deficiency was more common in neonates with early onset sepsis

*Vitamin D*

vitamin D deficiency [74].

<32 weeks [81].

PMA or discharge [68].

Cleveland area in US (latitude 410

last 3 decades in Cleveland area [12].

Seto and colleagues measured cord blood 25 [OH]D levels in 276 AA term infants and 162 term white infants and found that AA infants had a 3.6 greater adjusted odds of

Currently, there continues to be emerging information on the distribution of 25[OH]D levels in preterm neonates. A few studies have documented 25[OH]D levels from neonates at birth with sample sizes ranging from 8 to 278 neonates [2, 75–80] with mean 25[OH]D levels ranging from ~6.5 ng/mL among preterm neonates in the United Arab Emirates [78] to 26.8 ng/mL preterm neonates in Canada [10]. A recent study on 596 preterm infants from Ohio, USA reported median 25[OH]D level of 18.5 ng/mL for infants born at 34–36 weeks and 18.6 ng/mL for infants born

The levels of 25[OH]D between the mother and the fetus are positively correlated [68, 81, 82]. Kassai et al. found that mothers who gave birth to preterm neonates had significantly lower mean 25[OH]D blood levels compared to those mothers who gave birth at term. Also, preterm neonates had significantly lower 25[OH]D levels compared to term neonates [83]. A study by Burris et al. measured umbilical cord plasma levels of 25[OH]D in 471 infants born at <37 weeks. They found that babies born at <32 weeks are at increased risk for vitamin D deficiency (25[OH]D levels <20 ng/dL) compared to infants born between 32 and 37 weeks [79]. Monagni et al. studied 120 mother infant dyads at three children's hospitals in Ohio where neonates were delivered at <32 weeks. They not only found that low serum concentrations of 25[OH]D (defined as <50 nmol/L) was common in preterm neonates at admission (64%), but they also found that maternal 25[OH]D levels were lower in infants born at <28 weeks compared to those that were born between 28 and 32 weeks' gestation. Serum 25[OH]D concentrations in preterm infants directly correlated with maternal vitamin D status at the time of delivery. Low 25[OH]D levels were noted at either 36 weeks post-menstrual age (PMA) or at discharge in 40% of infants <28 weeks and 30% of infants between 28 and 32 weeks PMA. Even though infants received vitamin D supplementation from various sources and intake progressively increased during their hospitalization, only 60% received 400 IU vitamin D daily by 36 weeks

In contrast to the above studies, a Canadian study and an US study did not show any significant difference in vitamin-D status between term and preterm neonates [10, 81]. A study of 3731 term infants in Jordan revealed that 94% had vitamin D deficiency defined as 25[OH]D level < 50 nmol/L. Shahraki et al. found that 25[OH]D levels in preterm neonates were not significantly lower than term neonates. Over 50% of both the term and preterm infants in this study had vitamin D insufficiency and about 25% had vitamin D deficiency [82]. In a cohort born in

portion of vitamin-D deficiency and insufficiency among neonates at birth, 31% and 49% respectively. Notably, they noted low stores of vitamin D despite 75% of women reporting regular multivitamin intake during pregnancy. Vitamin D deficiency was found to be more common in AA neonates (63%) than Caucasian (27%) neonates [81]. Bodnar et.al studied 400 mother–infant pairs in Pittsburgh. They showed that nearly 50% of AA neonates and 10% of white neonates, had serum 25[OH]D levels at birth less than 15 ng/mL despite adequate compliance with a 400 IU daily vitamin-D intake by 90% of their mothers [22]. A prolonged winter season with limited sun exposure in Cleveland might be a contributing factor to the vitamin-D deficiency found in this population. There has been no significant improvement in the vitamin-D status among neonates born to AA women in the

N), Kanike et al. reported a remarkably high pro-

**30**

#### **7. Consequences of vitamin D deficiency in children**

Vitamin-D deficiency is the most common cause of rickets and also increases the risk of respiratory distress syndrome, lower respiratory infections, food sensitivities, asthma, type I diabetes, autism and schizophrenia [2, 3, 6, 8, 15]. Vitamin D deficiency in pregnancy impairs fetal lung development partially through suppressing type II pneumocyte differentiation increasing the risk of respiratory distress syndrome in the newborn period [84]. Furthermore, studies have shown that early onset sepsis and late onset sepsis occurs more frequently in term infants with vitamin D deficiency [85–87]. To highlight, one study by Singh and Chaudari found that vitamin D deficiency was more common in neonates with early onset sepsis and was associated with increased severity of sepsis and mortality [87].

Vitamin D deficiency prevents effective absorption of dietary calcium and phosphorus. Vitamin D stores in newborn are completely dependent on vitamin D supply from the mother [12]. Not surprisingly, poor maternal vitamin D status during pregnancy is a major risk factor for infant rickets [13, 88, 89]. Severe chronic vitamin D deficiency leads to overt skeletal abnormalities in children like rickets [90, 91]. However, neonates who are vitamin-D insufficient have no apparent skeletal or calcium metabolism abnormalities [16]. In developing countries rickets has been ranked among the five most prevalent diseases in children [92]. Poorer outcomes during pregnancy, at birth and during infancy are associated with lower serum 25[OH]D levels [24, 93]. Reduced bone mass at 9 years of age was seen in children born with low serum 25[OH]D concentrations [94].

There is conflicting data about role of vitamin D and neurodevelopmental outcomes. A meta-analysis by Tous and colleauges found that infants born to mothers with vitamin D insufficiency had lower scores in both mental and language development [95]. In contrast, Wang et al. found that vitamin D deficiency was not associated with neurodevelopment in infancy [84]. A prospective cohort study by McCarthy et al. found no association between antenatal 25[OH]D levels and neurodevelopmental outcomes at 5 years. Tous et al. found that maternal vitamin D deficiency is associated with lower birth weights, smaller head circumference, increased risk for small for gestational age (SGA) status, and preterm birth. Maternal vitamin D insufficiency was associated with increased risk for infants with SGA status and preterm birth [95]. Seto and colleagues found that black infants with vitamin D deficiency had 2.4 greater adjusted odds for SGA status at birth. The association between SGA and vitamin D deficiency was not demonstrated in white infants [74]. Furthermore, a systematic review by Pligt et al. found the maternal vitamin D deficiency was associated with low birth weight, SGA status at birth, stunting of growth immediately after delivery, and preterm birth [96].

#### **8. Recommended dietary intake in pregnant women and Newborn at risk for vitamin D deficiency**

As per the US federal government's 2020–2025 guidelines, fortified foods and dietary supplements are beneficial when it is impossible to meet needs for one or more nutrients during certain life stages such as pregnancy. Milk, many ready-to-eat cereals, and some brands of yogurt, orange juice and margarines are fortified with vitamin D. Trout, tuna, salmon, and mackerel are fatty fish with a high content of vitamin D. One tablespoon of cod liver oil has 1360 IU of vitamin D. Cheese, beef liver and egg yolks naturally contain small amounts of vitamin D. The United States

and Canada mandates the fortification of infant formula with 1–2.5 mcg/100 kcal (40–100 IU) vitamin D and 1–2 mcg/100 kcal (40–80 IU) respectively.

Global consensus recommendations on prevention and management of nutritional rickets states that pregnant women should receive 600 IU/d of vitamin-D, preferably as a combined preparation with other recommended micronutrients such as iron and folic acid [97]. The Endocrine Society clinical practice guidelines also recommend at least 600 IU/d of vitamin D in pregnant and lactating women. They also recognize that 1500–2000 IU/day of vitamin D may be needed to maintain 25[OH]D levels>30 ng/mL [32]. However, the average prenatal supplements contain only 400 IU of vitamin D [97]. There is also mounting evidence of the importance of vitamin D supplementation to achieve serum 25[OH]D level of ≥40 ng/ml [55].

Rostami et al. evaluated the effectiveness of a prenatal screening study for optimizing vitamin-D status during pregnancy. The outcome of this program was the prevention of complications of pregnancy. They observed a > 25-fold increase in the number of pregnant women who were able to accomplish a 25[OH]D that was >20 ng/mL when they were screened for their vitamin-D status and provided supplementation compared with pregnant women who were not screened and consequently were not counseled to take vitamin-D supplements. They observed an outstanding decrease in adverse outcomes in pregnant women who were screened and received vitamin-D supplementation. They reported 60%, 50%, and 40% decreases in preeclampsia, gestational diabetes, and preterm delivery, respectively [98].

A recent Cochrane review on Vitamin D supplementation in pregnancy included 30 clinical studies on 3700 pregnant women and reported that taking vitamin D supplements in pregnancy probably reduces the risk of pre-eclampsia, gestational diabetes, post-partum hemorrhage and low-birthweight infant, but there was no difference in the risk of preterm birth before 37 weeks. They also reported that taking vitamin D and calcium together in pregnancy may increase the risk of preterm birth. These results warrant further research [99]. Prenatal supplementation with 4400 IU daily decreased the incidence of asthma and recurrent wheezing in these children at age 3 years by 6.1% [100].

In the 2020 WHO guidelines, routine oral supplementation of vitamin D is not recommended for pregnant women to improve maternal and perinatal outcomes. Pregnant women should be encouraged to receive adequate nutrition, which is best achieved through consumption of a healthy, balanced diet. Pregnant women should be advised that sunlight is the most important source of vitamin D. The amount of time needed in the sun is not known and depends on many variables, such as the amount of skin exposed, the time of day, latitude and season, skin pigmentation and sunscreen use. For pregnant women with suspected vitamin D deficiency, vitamin D supplements may be given at the current recommended nutrient intake of 200 IU per day. This may include women in populations where direct sun exposure is limited.

#### **9. Conclusion**

Vitamin D status is more significant during pregnancy, affecting not only the mother but also her growing fetus, and later, her growing child. There are variations in vitamin D status based on gestation at birth, global region of birth, race, and maternal vitamin D status during pregnancy. The current literature suggests that neonates are at high risk of vitamin-D deficiency, even when mothers are compliant with prenatal vitamins. Current prenatal vitamins may not contain enough vitamin-D to prevent deficiency. There has been substantial debate surrounding

**33**

**Author details**

Neelakanta Kanike1

\*, Naveen Kannekanti<sup>2</sup>

University, MetroHealth Medical Center, Cleveland, OH, USA

\*Address all correspondence to: neelkanike@gmail.com

provided the original work is properly cited.

Medicine, The Women's Hospital-Deaconess, Newburgh, IN, USA

1 Department of Pediatrics, Division of Neonatology, Indiana University School of

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Department of Pediatrics, Division of Neonatology, Case Western Reserve

and Jenny Camacho1

*Vitamin D Deficiency in Pregnant Women and Newborn DOI: http://dx.doi.org/10.5772/intechopen.98454*

pregnant women and their newborn infants.

**Conflicts of interest statement**

interest to disclose.

aspects of the work.

**Author contributions**

the daily requirement of vitamin D and what constitutes sufficiency during pregnancy. Higher-dose supplementation may be needed to improve maternal and neonatal vitamin-D status. Future multicenter studies are needed to determine the minimum dose of vitamin-D requirements during pregnancy to achieve vitamin-D sufficiency. It is time to rethink our approach to ensure vitamin-D sufficiency in

The authors have indicated no financial relationships relevant to this article to disclose. The authors have indicated they have no potential/perceived conflicts of

N.K and J.C conceptualized and drafted the initial manuscript and reviewed and revised the manuscript. N.KG reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all

*Vitamin D Deficiency in Pregnant Women and Newborn DOI: http://dx.doi.org/10.5772/intechopen.98454*

the daily requirement of vitamin D and what constitutes sufficiency during pregnancy. Higher-dose supplementation may be needed to improve maternal and neonatal vitamin-D status. Future multicenter studies are needed to determine the minimum dose of vitamin-D requirements during pregnancy to achieve vitamin-D sufficiency. It is time to rethink our approach to ensure vitamin-D sufficiency in pregnant women and their newborn infants.

#### **Conflicts of interest statement**

The authors have indicated no financial relationships relevant to this article to disclose. The authors have indicated they have no potential/perceived conflicts of interest to disclose.

#### **Author contributions**

*Vitamin D*

respectively [98].

direct sun exposure is limited.

**9. Conclusion**

and Canada mandates the fortification of infant formula with 1–2.5 mcg/100 kcal

A recent Cochrane review on Vitamin D supplementation in pregnancy included 30 clinical studies on 3700 pregnant women and reported that taking vitamin D supplements in pregnancy probably reduces the risk of pre-eclampsia, gestational diabetes, post-partum hemorrhage and low-birthweight infant, but there was no difference in the risk of preterm birth before 37 weeks. They also reported that taking vitamin D and calcium together in pregnancy may increase the risk of preterm birth. These results warrant further research [99]. Prenatal supplementation with 4400 IU daily decreased the incidence of asthma and recur-

In the 2020 WHO guidelines, routine oral supplementation of vitamin D is not recommended for pregnant women to improve maternal and perinatal outcomes. Pregnant women should be encouraged to receive adequate nutrition, which is best achieved through consumption of a healthy, balanced diet. Pregnant women should be advised that sunlight is the most important source of vitamin D. The amount of time needed in the sun is not known and depends on many variables, such as the amount of skin exposed, the time of day, latitude and season, skin pigmentation and sunscreen use. For pregnant women with suspected vitamin D deficiency, vitamin D supplements may be given at the current recommended nutrient intake of 200 IU per day. This may include women in populations where

Vitamin D status is more significant during pregnancy, affecting not only the mother but also her growing fetus, and later, her growing child. There are variations in vitamin D status based on gestation at birth, global region of birth, race, and maternal vitamin D status during pregnancy. The current literature suggests that neonates are at high risk of vitamin-D deficiency, even when mothers are compliant with prenatal vitamins. Current prenatal vitamins may not contain enough vitamin-D to prevent deficiency. There has been substantial debate surrounding

rent wheezing in these children at age 3 years by 6.1% [100].

Global consensus recommendations on prevention and management of nutritional rickets states that pregnant women should receive 600 IU/d of vitamin-D, preferably as a combined preparation with other recommended micronutrients such as iron and folic acid [97]. The Endocrine Society clinical practice guidelines also recommend at least 600 IU/d of vitamin D in pregnant and lactating women. They also recognize that 1500–2000 IU/day of vitamin D may be needed to maintain 25[OH]D levels>30 ng/mL [32]. However, the average prenatal supplements contain only 400 IU of vitamin D [97]. There is also mounting evidence of the importance of vitamin D supplementation to achieve serum 25[OH]D level of ≥40 ng/ml [55]. Rostami et al. evaluated the effectiveness of a prenatal screening study for optimizing vitamin-D status during pregnancy. The outcome of this program was the prevention of complications of pregnancy. They observed a > 25-fold increase in the number of pregnant women who were able to accomplish a 25[OH]D that was >20 ng/mL when they were screened for their vitamin-D status and provided supplementation compared with pregnant women who were not screened and consequently were not counseled to take vitamin-D supplements. They observed an outstanding decrease in adverse outcomes in pregnant women who were screened and received vitamin-D supplementation. They reported 60%, 50%, and 40% decreases in preeclampsia, gestational diabetes, and preterm delivery,

(40–100 IU) vitamin D and 1–2 mcg/100 kcal (40–80 IU) respectively.

**32**

N.K and J.C conceptualized and drafted the initial manuscript and reviewed and revised the manuscript. N.KG reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

### **Author details**

Neelakanta Kanike1 \*, Naveen Kannekanti<sup>2</sup> and Jenny Camacho1

1 Department of Pediatrics, Division of Neonatology, Indiana University School of Medicine, The Women's Hospital-Deaconess, Newburgh, IN, USA

2 Department of Pediatrics, Division of Neonatology, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, USA

\*Address all correspondence to: neelkanike@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

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[3] Camargo CA, Jr., Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR, Kleinman K, Gillman MW: **Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age.** Am J Clin Nutr 2007, **85:**788-795.

[4] Camargo CA, Jr., Ingham T, Wickens K, Thadhani R, Silvers KM, Epton MJ, Town GI, Pattemore PK, Espinola JA, Crane J, et al: **Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma.** Pediatrics 2011, **127:**e180-e187.

[5] Stene LC, Joner G, Norwegian Childhood Diabetes Study G: **Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study.** Am J Clin Nutr 2003, **78:**1128-1134.

[6] Sorensen IM, Joner G, Jenum PA, Eskild A, Torjesen PA, Stene LC: **Maternal serum levels of 25-hydroxyvitamin D during pregnancy and risk of type 1 diabetes in the offspring.** Diabetes 2012, **61:**175-178.

[7] McGrath J, Saari K, Hakko H, Jokelainen J, Jones P, Jarvelin MR, Chant D, Isohanni M: **Vitamin D supplementation during the first year**  **of life and risk of schizophrenia: a Finnish birth cohort study.** Schizophr Res 2004, **67:**237-245.

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[9] Vinkhuyzen AAE, Eyles DW, Burne THJ, Blanken LME, Kruithof CJ, Verhulst F, Jaddoe VW, Tiemeier H, McGrath JJ: **Gestational vitamin D deficiency and autism-related traits: the Generation R Study.** Mol Psychiatry 2018, **23:**240-246.

[10] Morgan C, Dodds L, Langille DB, Weiler HA, Armson BA, Forest JC, Giguere Y, Woolcott CG: **Cord blood vitamin D status and neonatal outcomes in a birth cohort in Quebec, Canada.** Arch Gynecol Obstet 2016, **293:**731-738.

[11] Kovacs CS: **Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies.** Am J Clin Nutr 2008, **88:**520S-528S.

[12] Hollis BW, Pittard WB, 3rd: **Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences.** J Clin Endocrinol Metab 1984, **59:**652-657.

[13] Specker BL: **Do North American women need supplemental vitamin D during pregnancy or lactation?** *Am J Clin Nutr* 1994, **59:**484S-490S; discussion 490S-491S.

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[15] Wharton B, Bishop N: **Rickets.** Lancet 2003, **362:**1389-1400.

[16] Holick MF: **Resurrection of vitamin D deficiency and rickets.** J Clin Invest 2006, **116:**2062-2072.

[17] Calvo MS, Whiting SJ: **Prevalence of vitamin D insufficiency in Canada and the United States: importance to health status and efficacy of current food fortification and dietary supplement use.** Nutr Rev 2003, **61:**107-113.

[18] Hanley DA, Davison KS: **Vitamin D insufficiency in North America.** J Nutr 2005, **135:**332-337.

[19] Holick MF: **Vitamin D: A millenium perspective.** J Cell Biochem 2003, **88:**296-307.

[20] Holick MF: **The vitamin D epidemic and its health consequences.** J Nutr 2005, **135:**2739S-2748S.

[21] Kumar J, Muntner P, Kaskel FJ, Hailpern SM, Melamed ML: **Prevalence and associations of 25-hydroxy vitamin D deficiency in US children: NHANES 2001-2004.** Pediatrics 2009, **124:**e362-e370.

[22] Bodnar LM, Simhan HN, Powers RW, Frank MP, Cooperstein E, Roberts JM: **High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern United States and their neonates.** J Nutr 2007, **137:**447-452.

[23] Johnson DD, Wagner CL, Hulsey TC, McNeil RB, Ebeling M, Hollis BW: **Vitamin D deficiency and insufficiency is common during pregnancy.** Am J Perinatol 2011, **28:**7-12.

[24] Saraf R, Morton SM, Camargo CA, Jr., Grant CC: **Global summary of maternal and newborn vitamin D** 

**status - a systematic review.** Matern Child Nutr 2016, **12:**647-668.

[25] Holick MF: **Vitamin D deficiency.** N Engl J Med 2007, **357:**266-281.

[26] DeLuca HF: **Overview of general physiologic features and functions of vitamin D.** Am J Clin Nutr 2004, **80:**1689S-1696S.

[27] Christakos S, Dhawan P, Liu Y, Peng X, Porta A: **New insights into the mechanisms of vitamin D action.** J Cell Biochem 2003, **88:**695-705.

[28] Heaney RP: **Functional indices of vitamin D status and ramifications of vitamin D deficiency.** Am J Clin Nutr 2004, **80:**1706S-1709S.

[29] Dusso AS, Brown AJ, Slatopolsky E: **Vitamin D.** Am J Physiol Renal Physiol 2005, **289:**F8-28.

[30] Lee JM, Smith JR, Philipp BL, Chen TC, Mathieu J, Holick MF: **Vitamin D deficiency in a healthy group of mothers and newborn infants.** Clin Pediatr (Phila) 2007, **46:**42-44.

[31] Merewood A, Mehta SD, Grossman X, Chen TC, Mathieu JS, Holick MF, Bauchner H: **Widespread vitamin D deficiency in urban Massachusetts newborns and their mothers.** Pediatrics 2010, **125:**640-647.

[32] Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine S: **Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.** J Clin Endocrinol Metab 2011, **96:** 1911-1930.

[33] Gartner LM, Greer FR, Section on B, Committee on Nutrition. American Academy of P: **Prevention of rickets and vitamin D deficiency: new** 

**34**

*Vitamin D*

**References**

**18:**153-165.

[1] Holick MF: **The vitamin D** 

**deficiency pandemic: Approaches for diagnosis, treatment and prevention.** Rev Endocr Metab Disord 2017,

**of life and risk of schizophrenia: a Finnish birth cohort study.** Schizophr

[8] Vinkhuyzen AAE, Eyles DW, Burne THJ, Blanken LME, Kruithof CJ, Verhulst F, White T, Jaddoe VW, Tiemeier H, McGrath JJ: **Gestational vitamin D deficiency and autism spectrum disorder.** BJPsych Open 2017,

[9] Vinkhuyzen AAE, Eyles DW, Burne THJ, Blanken LME, Kruithof CJ, Verhulst F, Jaddoe VW, Tiemeier H, McGrath JJ: **Gestational vitamin D deficiency and autism-related traits:** 

**the Generation R Study.** Mol Psychiatry 2018, **23:**240-246.

[10] Morgan C, Dodds L, Langille DB, Weiler HA, Armson BA, Forest JC, Giguere Y, Woolcott CG: **Cord blood vitamin D status and neonatal** 

**outcomes in a birth cohort in Quebec, Canada.** Arch Gynecol Obstet 2016,

[11] Kovacs CS: **Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies.** Am J Clin Nutr 2008,

[12] Hollis BW, Pittard WB, 3rd: **Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences.** J Clin Endocrinol Metab 1984, **59:**652-657.

[13] Specker BL: **Do North American women need supplemental vitamin D during pregnancy or lactation?** *Am J Clin Nutr* 1994, **59:**484S-490S;

[14] Harrison HE: **A tribute to the first lady of public health (Martha M. Eliot). V. The disappearance of rickets.** Am J Public Health Nations Health 1966,

discussion 490S-491S.

**56:**734-737.

Res 2004, **67:**237-245.

**3:**85-90.

**293:**731-738.

**88:**520S-528S.

[2] Mohamed Hegazy A, Mohamed Shinkar D, Refaat Mohamed N, Abdalla Gaber H: **Association between serum 25 (OH) vitamin D level at birth and respiratory morbidities among preterm neonates.** J Matern Fetal Neonatal Med 2018, **31:**2649-2655.

[3] Camargo CA, Jr., Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR, Kleinman K, Gillman MW: **Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age.** Am J Clin Nutr 2007, **85:**788-795.

[4] Camargo CA, Jr., Ingham T, Wickens K, Thadhani R, Silvers KM, Epton MJ, Town GI, Pattemore PK, Espinola JA, Crane J, et al: **Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing,** 

**and asthma.** Pediatrics 2011,

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**study.** Am J Clin Nutr 2003,

Diabetes 2012, **61:**175-178.

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[6] Sorensen IM, Joner G, Jenum PA, Eskild A, Torjesen PA, Stene LC: **Maternal serum levels of 25-hydroxyvitamin D during pregnancy and risk of type 1 diabetes in the offspring.**

**127:**e180-e187.

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[35] Lips P, Cashman KD, Lamberg-Allardt C, Bischoff-Ferrari HA, Obermayer-Pietsch B, Bianchi ML, Stepan J, El-Hajj Fuleihan G, Bouillon R: **Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society.** Eur J Endocrinol 2019, **180:**P23-P54.

[36] Cashman KD, Dowling KG, Skrabakova Z, Gonzalez-Gross M, Valtuena J, De Henauw S, Moreno L, Damsgaard CT, Michaelsen KF, Molgaard C, et al: **Vitamin D deficiency in Europe: pandemic?** Am J Clin Nutr 2016, **103:**1033-1044.

[37] van der Meer IM, Karamali NS, Boeke AJ, Lips P, Middelkoop BJ, Verhoeven I, Wuister JD: **High prevalence of vitamin D deficiency in pregnant non-Western women in The Hague, Netherlands.** Am J Clin Nutr 2006, **84:**350-353; quiz 468-359.

[38] Mutlu N, Esra H, Begum A, Fatma D, Arzu Y, Yalcin H, Fatih K, Selahattin K: **Relation of maternal vitamin D status with gestational diabetes mellitus and perinatal outcome.** Afr Health Sci 2015, **15:**523-531.

[39] Tao M, Shao H, Gu J, Zhen Z: **Vitamin D status of pregnant women in Shanghai, China.** J Matern Fetal Neonatal Med 2012, **25:**237-239.

[40] Palacios C, De-Regil LM, Lombardo LK, Peña-Rosas JP: **Vitamin D supplementation during pregnancy: Updated meta-analysis on maternal** 

**outcomes.** J Steroid Biochem Mol Biol 2016, **164:**148-155.

[41] Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, El-Hajj Fuleihan G, Josse RG, Lips P, Morales-Torres J, Group IOFCoSANW: **Global vitamin D status and determinants of hypovitaminosis D.** Osteoporos Int 2009, **20:**1807-1820.

[42] Balasubramanian S, Dhanalakshmi K, Amperayani S: **Vitamin D deficiency in childhood-a review of current guidelines on diagnosis and management.** Indian Pediatr 2013, **50:**669-675.

[43] Joiner TA, Foster C, Shope T: **The many faces of vitamin D deficiency rickets.** Pediatr Rev 2000, **21:**296-302.

[44] Harinarayan CV, Joshi SR: **Vitamin D status in India--its implications and remedial measures.** J Assoc Physicians India 2009, **57:**40-48.

[45] Chacham S, Rajput S, Gurnurkar S, Mirza A, Saxena V, Dakshinamurthy S, Chaturvedi J, Goyal JP, Chegondi M: **Prevalence of Vitamin D Deficiency Among Infants in Northern India: A Hospital Based Prospective Study.** Cureus 2020, **12:**e11353.

[46] Mogire RM, Mutua A, Kimita W, Kamau A, Bejon P, Pettifor JM, Adeyemo A, Williams TN, Atkinson SH: **Prevalence of vitamin D deficiency in Africa: a systematic review and meta-analysis.** Lancet Glob Health 2020, **8:**e134-e142.

[47] Zhang W, Stoecklin E, Eggersdorfer M: **A glimpse of vitamin D status in Mainland China.** Nutrition 2013, **29:**953-957.

[48] Cyprian F, Lefkou E, Varoudi K, Girardi G: **Immunomodulatory Effects of Vitamin D in Pregnancy and Beyond.** Front Immunol 2019, **10:** 2739.

**37**

**86:**112-123.

*Vitamin D Deficiency in Pregnant Women and Newborn DOI: http://dx.doi.org/10.5772/intechopen.98454*

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[58] Carmeliet G, Bouillon R: **How Important Is Vitamin D for Calcium Homeostasis During Pregnancy and Lactation?** J Bone Miner Res 2018,

[59] Sachan A, Gupta R, Das V,

Nutr 2005, **81:**1060-1064.

[60] Agarwal KS, Mughal MZ, Upadhyay P, Berry JL, Mawer EB, Puliyel JM: **The impact of atmospheric pollution on vitamin D status of infants and toddlers in Delhi, India.** Arch Dis Child 2002, **87:**111-113.

[61] Sowah D, Fan X, Dennett L,

**and deficiency with different occupations: a systematic review.** BMC Public Health 2017, **17:**519.

**9:**e111265.

Hagtvedt R, Straube S: **Vitamin D levels** 

[62] Ekwaru JP, Zwicker JD, Holick MF, Giovannucci E, Veugelers PJ: **The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers.** PLoS One 2014,

[63] Earthman CP, Beckman LM, Masodkar K, Sibley SD: **The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications.** Int J

Obes (Lond) 2012, **36:**387-396.

[64] Lin E, Armstrong-Moore D, Liang Z, Sweeney JF, Torres WE, Ziegler TR, Tangpricha V, Gletsu-Miller

Agarwal A, Awasthi PK, Bhatia V: **High prevalence of vitamin D deficiency among pregnant women and their newborns in northern India.** Am J Clin

**236:**R93-R103.

**33:**13-15.

[49] Kiely ME, Wagner CL, Roth DE: **Vitamin D in pregnancy: Where we are and where we should go.** J Steroid Biochem Mol Biol 2020, **201:**105669.

[50] Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O'Beirne M, Rabi DM: **Association between** 

[51] Autier P, Gandini S: **Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.** Arch Intern Med

[52] Pilz S, Tomaschitz A, Obermayer-Pietsch B, Dobnig H, Pieber TR: **Epidemiology of vitamin D** 

**insufficiency and cancer mortality.** Anticancer Res 2009, **29:**3699-3704.

[53] Chen YH, Liu ZB, Ma L, Zhang ZC, Fu L, Yu Z, Chen W, Song YP, Wang P, Wang H, Xu X: **Gestational vitamin D** 

**insufficiency and fetal intrauterine growth restriction partially through inducing placental inflammation.** J Steroid Biochem Mol Biol 2020,

[54] Kovacs CS: **Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones.** Physiol Rev

**requirements during pregnancy.** Bone

[56] Karras SN, Wagner CL, Castracane

[55] Hollis BW, Wagner CL: **New insights into the vitamin D** 

VD: **Understanding vitamin D metabolism in pregnancy: From physiology to pathophysiology and clinical outcomes.** Metabolism 2018,

**deficiency causes placental** 

**203:**105733.

2014, **94:**1143-1218.

Res 2017, **5:**17030.

2007, **167:**1730-1737.

**maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies.** BMJ 2013, **346:**f1169.

*Vitamin D Deficiency in Pregnant Women and Newborn DOI: http://dx.doi.org/10.5772/intechopen.98454*

[49] Kiely ME, Wagner CL, Roth DE: **Vitamin D in pregnancy: Where we are and where we should go.** J Steroid Biochem Mol Biol 2020, **201:**105669.

*Vitamin D*

**guidelines for vitamin D intake.** Pediatrics 2003, **111:**908-910.

Nutr 2019, **110:**150-157.

[34] Herrick KA, Storandt RJ, Afful J, Pfeiffer CM, Schleicher RL, Gahche JJ, Potischman N: **Vitamin D status in the United States, 2011-2014.** Am J Clin

**outcomes.** J Steroid Biochem Mol Biol

[41] Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, El-Hajj Fuleihan G,

Josse RG, Lips P, Morales-Torres J, Group IOFCoSANW: **Global vitamin D status and determinants of hypovitaminosis D.** Osteoporos Int 2009, **20:**1807-1820.

2016, **164:**148-155.

[42] Balasubramanian S,

Pediatr 2013, **50:**669-675.

India 2009, **57:**40-48.

Cureus 2020, **12:**e11353.

2020, **8:**e134-e142.

**29:**953-957.

2739.

Dhanalakshmi K, Amperayani S: **Vitamin D deficiency in childhood-a review of current guidelines on diagnosis and management.** Indian

[43] Joiner TA, Foster C, Shope T: **The many faces of vitamin D deficiency rickets.** Pediatr Rev 2000, **21:**296-302.

[44] Harinarayan CV, Joshi SR: **Vitamin D status in India--its implications and remedial measures.** J Assoc Physicians

[45] Chacham S, Rajput S, Gurnurkar S, Mirza A, Saxena V, Dakshinamurthy S, Chaturvedi J, Goyal JP, Chegondi M: **Prevalence of Vitamin D Deficiency Among Infants in Northern India: A Hospital Based Prospective Study.**

[46] Mogire RM, Mutua A, Kimita W, Kamau A, Bejon P, Pettifor JM,

Adeyemo A, Williams TN, Atkinson SH: **Prevalence of vitamin D deficiency in Africa: a systematic review and meta-analysis.** Lancet Glob Health

[47] Zhang W, Stoecklin E, Eggersdorfer M: **A glimpse of vitamin D status in Mainland China.** Nutrition 2013,

[48] Cyprian F, Lefkou E, Varoudi K, Girardi G: **Immunomodulatory Effects** 

**of Vitamin D in Pregnancy and Beyond.** Front Immunol 2019, **10:**

[35] Lips P, Cashman KD, Lamberg-Allardt C, Bischoff-Ferrari HA, Obermayer-Pietsch B, Bianchi ML, Stepan J, El-Hajj Fuleihan G, Bouillon R: **Current vitamin D status in European** 

**and Middle East countries and strategies to prevent vitamin D** 

[36] Cashman KD, Dowling KG, Skrabakova Z, Gonzalez-Gross M, Valtuena J, De Henauw S, Moreno L, Damsgaard CT, Michaelsen KF,

2016, **103:**1033-1044.

**deficiency: a position statement of the European Calcified Tissue Society.** Eur J Endocrinol 2019, **180:**P23-P54.

Molgaard C, et al: **Vitamin D deficiency in Europe: pandemic?** Am J Clin Nutr

[37] van der Meer IM, Karamali NS, Boeke AJ, Lips P, Middelkoop BJ, Verhoeven I, Wuister JD: **High** 

[38] Mutlu N, Esra H, Begum A, Fatma D, Arzu Y, Yalcin H, Fatih K, Selahattin K: **Relation of maternal vitamin D status with gestational diabetes mellitus and perinatal outcome.** Afr Health Sci 2015,

[39] Tao M, Shao H, Gu J, Zhen Z: **Vitamin D status of pregnant women in Shanghai, China.** J Matern Fetal Neonatal Med 2012, **25:**237-239.

[40] Palacios C, De-Regil LM,

Lombardo LK, Peña-Rosas JP: **Vitamin D supplementation during pregnancy: Updated meta-analysis on maternal** 

**prevalence of vitamin D deficiency in pregnant non-Western women in The Hague, Netherlands.** Am J Clin Nutr 2006, **84:**350-353; quiz 468-359.

**36**

**15:**523-531.

[50] Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O'Beirne M, Rabi DM: **Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies.** BMJ 2013, **346:**f1169.

[51] Autier P, Gandini S: **Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.** Arch Intern Med 2007, **167:**1730-1737.

[52] Pilz S, Tomaschitz A, Obermayer-Pietsch B, Dobnig H, Pieber TR: **Epidemiology of vitamin D insufficiency and cancer mortality.** Anticancer Res 2009, **29:**3699-3704.

[53] Chen YH, Liu ZB, Ma L, Zhang ZC, Fu L, Yu Z, Chen W, Song YP, Wang P, Wang H, Xu X: **Gestational vitamin D deficiency causes placental insufficiency and fetal intrauterine growth restriction partially through inducing placental inflammation.** J Steroid Biochem Mol Biol 2020, **203:**105733.

[54] Kovacs CS: **Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones.** Physiol Rev 2014, **94:**1143-1218.

[55] Hollis BW, Wagner CL: **New insights into the vitamin D requirements during pregnancy.** Bone Res 2017, **5:**17030.

[56] Karras SN, Wagner CL, Castracane VD: **Understanding vitamin D metabolism in pregnancy: From physiology to pathophysiology and clinical outcomes.** Metabolism 2018, **86:**112-123.

[57] Ganguly A, Tamblyn JA, Finn-Sell S, Chan SY, Westwood M, Gupta J, Kilby MD, Gross SR, Hewison M: **Vitamin D, the placenta and early pregnancy: effects on trophoblast function.** J Endocrinol 2018, **236:**R93-R103.

[58] Carmeliet G, Bouillon R: **How Important Is Vitamin D for Calcium Homeostasis During Pregnancy and Lactation?** J Bone Miner Res 2018, **33:**13-15.

[59] Sachan A, Gupta R, Das V, Agarwal A, Awasthi PK, Bhatia V: **High prevalence of vitamin D deficiency among pregnant women and their newborns in northern India.** Am J Clin Nutr 2005, **81:**1060-1064.

[60] Agarwal KS, Mughal MZ, Upadhyay P, Berry JL, Mawer EB, Puliyel JM: **The impact of atmospheric pollution on vitamin D status of infants and toddlers in Delhi, India.** Arch Dis Child 2002, **87:**111-113.

[61] Sowah D, Fan X, Dennett L, Hagtvedt R, Straube S: **Vitamin D levels and deficiency with different occupations: a systematic review.** BMC Public Health 2017, **17:**519.

[62] Ekwaru JP, Zwicker JD, Holick MF, Giovannucci E, Veugelers PJ: **The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers.** PLoS One 2014, **9:**e111265.

[63] Earthman CP, Beckman LM, Masodkar K, Sibley SD: **The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications.** Int J Obes (Lond) 2012, **36:**387-396.

[64] Lin E, Armstrong-Moore D, Liang Z, Sweeney JF, Torres WE, Ziegler TR, Tangpricha V, Gletsu-Miller N: **Contribution of adipose tissue to plasma 25-hydroxyvitamin D concentrations during weight loss following gastric bypass surgery.** Obesity (Silver Spring) 2011, **19:**588-594.

[65] Pappa HM, Bern E, Kamin D, Grand RJ: **Vitamin D status in gastrointestinal and liver disease.** Curr Opin Gastroenterol 2008, **24:**176-183.

[66] Sotunde OF, Laliberte A, Weiler HA: **Maternal risk factors and newborn infant vitamin D status: a scoping literature review.** Nutr Res 2019, **63:**1-20.

[67] Urrutia-Pereira M, Sole D: **[Vitamin D deficiency in pregnancy and its impact on the fetus, the newborn and in childhood].** Rev Paul Pediatr 2015, **33:**104-113.

[68] Monangi N, Slaughter JL, Dawodu A, Smith C, Akinbi HT: **Vitamin D status of early preterm infants and the effects of vitamin D intake during hospital stay.** Arch Dis Child Fetal Neonatal Ed 2014, **99:**F166-F168.

[69] Hilger J, Friedel A, Herr R, Rausch T, Roos F, Wahl DA, Pierroz DD, Weber P, Hoffmann K: **A systematic review of vitamin D status in populations worldwide.** Br J Nutr 2014, **111:**23-45.

[70] Arabi A, El Rassi R, El-Hajj Fuleihan G: **Hypovitaminosis D in developing countries-prevalence, risk factors and outcomes.** Nat Rev Endocrinol 2010, **6:**550-561.

[71] Taylor SN, Wagner CL, Fanning D, Quinones L, Hollis BW: **Vitamin D status as related to race and feeding type in preterm infants.** Breastfeed Med 2006, **1:**156-163.

[72] Basile LA, Taylor SN, Wagner CL, Quinones L, Hollis BW: **Neonatal** 

**vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency.** J Perinatol 2007, **27:**568-571.

[73] Hanson C, Armas L, Lyden E, Anderson-Berry A: **Vitamin D status and associations in newborn formulafed infants during initial hospitalization.** J Am Diet Assoc 2011, **111:**1836-1843.

[74] Seto TL, Tabangin ME, Langdon G, Mangeot C, Dawodu A, Steinhoff M, Narendran V: **Racial disparities in cord blood vitamin D levels and its association with small-forgestational-age infants.** J Perinatol 2016, **36:**623-628.

[75] Backstrom MC, Maki R, Kuusela AL, Sievanen H, Koivisto AM, Ikonen RS, Kouri T, Maki M: **Randomised controlled trial of vitamin D supplementation on bone density and biochemical indices in preterm infants.** Arch Dis Child Fetal Neonatal Ed 1999, **80:**F161-F166.

[76] Delmas PD, Glorieux FH, Delvin EE, Salle BL, Melki I: **Perinatal serum bone Gla-protein and vitamin D metabolites in preterm and fullterm neonates.** J Clin Endocrinol Metab 1987, **65:**588-591.

[77] Salle BL, Glorieux FH, Delvin EE, David LS, Meunier G: **Vitamin D metabolism in preterm infants. Serial serum calcitriol values during the first four days of life.** Acta Paediatr Scand 1983, **72:**203-206.

[78] Dawodu A, Nath R: **High prevalence of moderately severe vitamin D deficiency in preterm infants.** Pediatr Int 2011, **53:**207-210.

[79] Burris HH, Van Marter LJ, McElrath TF, Tabatabai P, Litonjua AA, Weiss ST, Christou H: **Vitamin D status among preterm and full-term infants at birth.** Pediatr Res 2014, **75:** 75-80.

**39**

**38:**193-197.

2019, **65:**609-616.

Pediatr 2020, **57:**232-234.

*Vitamin D Deficiency in Pregnant Women and Newborn DOI: http://dx.doi.org/10.5772/intechopen.98454*

> [88] Zeghoud F, Vervel C, Guillozo H, Walrant-Debray O, Boutignon H, Garabedian M: **Subclinical vitamin D deficiency in neonates: definition and response to vitamin D supplements.** Am J Clin Nutr 1997, **65:**771-778.

> [89] Wagner CL, Greer FR, American Academy of Pediatrics Section on B, American Academy of Pediatrics Committee on N: **Prevention of rickets and vitamin D deficiency in infants, children, and adolescents.** Pediatrics

2008, **122:**1142-1152.

1984, **73:**225-231.

**34:**537-553, vii.

**88:**720-755.

36-53.

1991, **325:**1875-1877.

Lancet 2006, **367:**36-43.

[90] Markestad T, Halvorsen S, Halvorsen KS, Aksnes L, Aarskog D: **Plasma concentrations of vitamin D metabolites before and during treatment of vitamin D deficiency rickets in children.** Acta Paediatr Scand

[92] Glorieux FH: **Rickets, the continuing challenge.** N Engl J Med

[93] Hossein-nezhad A, Holick MF: **Vitamin D for health: a global perspective.** Mayo Clin Proc 2013,

[94] Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, Arden NK, Godfrey KM, Cooper C, Princess Anne Hospital Study G: **Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study.**

[95] Tous M, Villalobos M, Iglesias L, Fernandez-Barres S, Arija V: **Vitamin D status during pregnancy and offspring outcomes: a systematic review and meta-analysis of observational studies.** Eur J Clin Nutr 2020, **74:**

[91] Pettifor JM: **Rickets and vitamin D deficiency in children and adolescents.** Endocrinol Metab Clin North Am 2005,

[80] Park SH, Lee GM, Moon JE, Kim HM: **Severe vitamin D deficiency in preterm infants: maternal and neonatal clinical features.** Korean J

Pediatr 2015, **58:**427-433.

2020, **12**.

Sci 2020, **25:**21.

[83] Kassai MS, Cafeo FR,

Sarni ROS: **Vitamin D plasma concentrations in pregnant women and their preterm newborns.** BMC Pregnancy Childbirth 2018, **18:**412.

[84] Wang P, Tan ZX, Fu L, Fan YJ, Luo B, Zhang ZH, Xu S, Chen YH, Zhao H, Xu DX: **Gestational vitamin D** 

**deficiency impairs fetal lung development through suppressing type II pneumocyte differentiation.** Reprod Toxicol 2020, **94:**40-47.

[85] Dhandai R, Jajoo M, Singh A, Mandal A, Jain R: **Association of vitamin D deficiency with an** 

**increased risk of late-onset neonatal sepsis.** Paediatr Int Child Health 2018,

[86] Agrawal A, Gupta A, Shrivastava J: **Role of Vitamin-D Deficiency in Term Neonates with Late-Onset Sepsis: A Case-Control Study.** J Trop Pediatr

[87] Singh P, Chaudhari V: **Association of Early-Onset Sepsis and Vitamin D Deficiency in Term Neonates.** Indian

[81] Kanike N, Hospattankar KG, Sharma A, Worley S, Groh-Wargo S: **Prevalence of Vitamin D Deficiency in** 

**a Large Newborn Cohort from Northern United States and Effect of Intrauterine Drug Exposure.** Nutrients

[82] Shahraki AD, Hasanabadi MS, Dehkordi AF: **The a ssociation of 25-hydroxy Vitamin D level in mothers with term and preterm delivery and their neonates.** J Res Med

Affonso-Kaufman FA, Suano-Souza FI,

*Vitamin D Deficiency in Pregnant Women and Newborn DOI: http://dx.doi.org/10.5772/intechopen.98454*

[80] Park SH, Lee GM, Moon JE, Kim HM: **Severe vitamin D deficiency in preterm infants: maternal and neonatal clinical features.** Korean J Pediatr 2015, **58:**427-433.

*Vitamin D*

**19:**588-594.

2019, **63:**1-20.

**33:**104-113.

**99:**F166-F168.

**111:**23-45.

RJ: **Vitamin D status in** 

N: **Contribution of adipose tissue to plasma 25-hydroxyvitamin D concentrations during weight loss following gastric bypass surgery.** Obesity (Silver Spring) 2011,

**vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency.** J

**hospitalization.** J Am Diet Assoc 2011,

[74] Seto TL, Tabangin ME, Langdon G, Mangeot C, Dawodu A, Steinhoff M, Narendran V: **Racial disparities in cord** 

**blood vitamin D levels and its association with small-for-**

[75] Backstrom MC, Maki R,

Ikonen RS, Kouri T, Maki M: **Randomised controlled trial of vitamin D supplementation on bone density and biochemical indices in preterm infants.** Arch Dis Child Fetal Neonatal Ed 1999, **80:**F161-F166.

[76] Delmas PD, Glorieux FH,

Delvin EE, Salle BL, Melki I: **Perinatal serum bone Gla-protein and vitamin D metabolites in preterm and fullterm neonates.** J Clin Endocrinol Metab 1987,

[77] Salle BL, Glorieux FH, Delvin EE, David LS, Meunier G: **Vitamin D metabolism in preterm infants. Serial serum calcitriol values during the first four days of life.** Acta Paediatr Scand

**gestational-age infants.** J Perinatol

Kuusela AL, Sievanen H, Koivisto AM,

Perinatol 2007, **27:**568-571.

**fed infants during initial** 

**111:**1836-1843.

2016, **36:**623-628.

**65:**588-591.

1983, **72:**203-206.

[78] Dawodu A, Nath R: **High prevalence of moderately severe vitamin D deficiency in preterm infants.** Pediatr Int 2011, **53:**207-210.

[79] Burris HH, Van Marter LJ,

**at birth.** Pediatr Res 2014, **75:**

75-80.

McElrath TF, Tabatabai P, Litonjua AA, Weiss ST, Christou H: **Vitamin D status among preterm and full-term infants** 

[73] Hanson C, Armas L, Lyden E, Anderson-Berry A: **Vitamin D status and associations in newborn formula-**

[65] Pappa HM, Bern E, Kamin D, Grand

**gastrointestinal and liver disease.** Curr Opin Gastroenterol 2008, **24:**176-183.

[67] Urrutia-Pereira M, Sole D: **[Vitamin D deficiency in pregnancy and its impact on the fetus, the newborn and in childhood].** Rev Paul Pediatr 2015,

[68] Monangi N, Slaughter JL, Dawodu A, Smith C, Akinbi HT: **Vitamin D status of early preterm infants and the effects of vitamin D intake during hospital stay.** Arch Dis

Child Fetal Neonatal Ed 2014,

[69] Hilger J, Friedel A, Herr R,

[70] Arabi A, El Rassi R, El-Hajj Fuleihan G: **Hypovitaminosis D in developing countries-prevalence, risk** 

**factors and outcomes.** Nat Rev Endocrinol 2010, **6:**550-561.

Med 2006, **1:**156-163.

[71] Taylor SN, Wagner CL, Fanning D, Quinones L, Hollis BW: **Vitamin D status as related to race and feeding type in preterm infants.** Breastfeed

[72] Basile LA, Taylor SN, Wagner CL, Quinones L, Hollis BW: **Neonatal** 

Rausch T, Roos F, Wahl DA, Pierroz DD, Weber P, Hoffmann K: **A systematic review of vitamin D status in** 

**populations worldwide.** Br J Nutr 2014,

[66] Sotunde OF, Laliberte A, Weiler HA: **Maternal risk factors and newborn infant vitamin D status: a scoping literature review.** Nutr Res

**38**

[81] Kanike N, Hospattankar KG, Sharma A, Worley S, Groh-Wargo S: **Prevalence of Vitamin D Deficiency in a Large Newborn Cohort from Northern United States and Effect of Intrauterine Drug Exposure.** Nutrients 2020, **12**.

[82] Shahraki AD, Hasanabadi MS, Dehkordi AF: **The a ssociation of 25-hydroxy Vitamin D level in mothers with term and preterm delivery and their neonates.** J Res Med Sci 2020, **25:**21.

[83] Kassai MS, Cafeo FR, Affonso-Kaufman FA, Suano-Souza FI, Sarni ROS: **Vitamin D plasma concentrations in pregnant women and their preterm newborns.** BMC Pregnancy Childbirth 2018, **18:**412.

[84] Wang P, Tan ZX, Fu L, Fan YJ, Luo B, Zhang ZH, Xu S, Chen YH, Zhao H, Xu DX: **Gestational vitamin D deficiency impairs fetal lung development through suppressing type II pneumocyte differentiation.** Reprod Toxicol 2020, **94:**40-47.

[85] Dhandai R, Jajoo M, Singh A, Mandal A, Jain R: **Association of vitamin D deficiency with an increased risk of late-onset neonatal sepsis.** Paediatr Int Child Health 2018, **38:**193-197.

[86] Agrawal A, Gupta A, Shrivastava J: **Role of Vitamin-D Deficiency in Term Neonates with Late-Onset Sepsis: A Case-Control Study.** J Trop Pediatr 2019, **65:**609-616.

[87] Singh P, Chaudhari V: **Association of Early-Onset Sepsis and Vitamin D Deficiency in Term Neonates.** Indian Pediatr 2020, **57:**232-234.

[88] Zeghoud F, Vervel C, Guillozo H, Walrant-Debray O, Boutignon H, Garabedian M: **Subclinical vitamin D deficiency in neonates: definition and response to vitamin D supplements.** Am J Clin Nutr 1997, **65:**771-778.

[89] Wagner CL, Greer FR, American Academy of Pediatrics Section on B, American Academy of Pediatrics Committee on N: **Prevention of rickets and vitamin D deficiency in infants, children, and adolescents.** Pediatrics 2008, **122:**1142-1152.

[90] Markestad T, Halvorsen S, Halvorsen KS, Aksnes L, Aarskog D: **Plasma concentrations of vitamin D metabolites before and during treatment of vitamin D deficiency rickets in children.** Acta Paediatr Scand 1984, **73:**225-231.

[91] Pettifor JM: **Rickets and vitamin D deficiency in children and adolescents.** Endocrinol Metab Clin North Am 2005, **34:**537-553, vii.

[92] Glorieux FH: **Rickets, the continuing challenge.** N Engl J Med 1991, **325:**1875-1877.

[93] Hossein-nezhad A, Holick MF: **Vitamin D for health: a global perspective.** Mayo Clin Proc 2013, **88:**720-755.

[94] Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, Arden NK, Godfrey KM, Cooper C, Princess Anne Hospital Study G: **Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study.** Lancet 2006, **367:**36-43.

[95] Tous M, Villalobos M, Iglesias L, Fernandez-Barres S, Arija V: **Vitamin D status during pregnancy and offspring outcomes: a systematic review and meta-analysis of observational studies.** Eur J Clin Nutr 2020, **74:** 36-53.

*Vitamin D*

[96] van der Pligt P, Willcox J, Szymlek-Gay EA, Murray E, Worsley A, Daly RM: **Associations of Maternal Vitamin D Deficiency with Pregnancy and Neonatal Complications in Developing Countries: A Systematic Review.** Nutrients 2018, **10**.

[97] Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, Michigami T, Tiosano D, Mughal MZ, Makitie O, et al: **Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.** J Clin Endocrinol Metab 2016, **101:**394-415.

[98] Rostami M, Tehrani FR, Simbar M, Bidhendi Yarandi R, Minooee S, Hollis BW, Hosseinpanah F: **Effectiveness of Prenatal Vitamin D Deficiency Screening and Treatment Program: A Stratified Randomized Field Trial.** J Clin Endocrinol Metab 2018, **103:**2936-2948.

[99] Palacios C, Kostiuk LK, Pena-Rosas JP: **Vitamin D supplementation for women during pregnancy.** Cochrane Database Syst Rev 2019, **7:**CD008873.

[100] Litonjua AA, Carey VJ, Laranjo N, Harshfield BJ, McElrath TF, O'Connor GT, Sandel M, Iverson RE, Jr., Lee-Paritz A, Strunk RC, et al: **Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years: The VDAART Randomized Clinical Trial.** JAMA 2016, **315:**362-370.

**41**

factors.

**1. Introduction**

**Chapter 3**

**Abstract**

Vitamin D in Elderly

*and Ewa Marcinowska-Suchowierska*

**Keywords:** Vitamin D, pleiotropic effect, elderly, aging

Vitamin D is a fat-soluble vitamin mainly produced by the skin after sun exposure (cholecalciferol - vitamin D3) and can also be obtained from food (ergocalciferol-vitamin D2 and vitamin D3) or supplementation. In the liver, vitamin D (the term "vitamin D" refers both vit.D2 and vit.D3") is converted to 25-hydroxyvitamin D [25(OH)D]), also known as "calcidiol", the major circulating metabolite of vitamin D which can be measured in the blood. In the kidney, [25(OH)D] is converted by 1-alfa-hydroxylase into its active form called 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as "calcitriol", that plays a vital role in maintaining bone

*Malgorzata Kupisz-Urbańska, Jacek Łukaszkiewicz* 

Vitamin D deficiency is common in elderly people, especially in patients with comorbidity and polypharmcy. In this group, low vitamin D plasma concentration is related to osteoporosis, osteomalacia, sarcopenia and myalgia. Vitamin D status in geriatric population is an effect of joint interaction of all vitamin D metabolic pathways, aging processes and multimorbidity. Therefore, all factors interfering with individual metabolic stages may affect 25-hydroxyvitamin D plasma concentration. The known factors affecting vitamin D metabolism interfere with cytochrome CYP3A4 activity. The phenomenon of drugs and vitamin D interactions is observed first and foremost in patients with comorbidity. This is a typical example of the situation where a lack of "hard evidence" is not synonymous with the possible lack of adverse effects. Geriatric giants, such as sarcopenia (progressive and generalized loss of skeletal muscle mass and strength) or cognitive decline, strongly influence elderly patients. Sarcopenia is one of the musculoskeletal consequences of hypovitaminosis D. These consequences are related to a higher risk of adverse outcomes, such as fracture, physical disability, a poor quality of life and death. This can lead not only to an increased risk of falls and fractures, but is also one of the main causes of frailty syndrome in the aging population. Generally, Vitamin D plasma concentration is significantly lower in participants with osteoporosis and muscle deterioration. In some observational and uncontrolled treatment studies, vitamin D supplementation led to a reduction of proximal myopathy and muscle pain. The most positive results were found in subjects with severe vitamin D deficiency and in patients avoiding high doses of vitamin D. However, the role of vitamin D in muscle pathologies is not clear and research has provided conflicting results. This is most likely due to the heterogeneity of the subjects, vitamin D doses and environmental

## **Chapter 3** Vitamin D in Elderly

*Malgorzata Kupisz-Urbańska, Jacek Łukaszkiewicz and Ewa Marcinowska-Suchowierska*

#### **Abstract**

*Vitamin D*

[96] van der Pligt P, Willcox J,

**Review.** Nutrients 2018, **10**.

Clin Endocrinol Metab 2016,

[98] Rostami M, Tehrani FR, Simbar M, Bidhendi Yarandi R, Minooee S, Hollis BW, Hosseinpanah F:

**Effectiveness of Prenatal Vitamin D Deficiency Screening and Treatment Program: A Stratified Randomized Field Trial.** J Clin Endocrinol Metab

[99] Palacios C, Kostiuk LK, Pena-Rosas JP: **Vitamin D supplementation for women during pregnancy.** Cochrane Database Syst Rev 2019, **7:**CD008873.

[100] Litonjua AA, Carey VJ, Laranjo N,

O'Connor GT, Sandel M, Iverson RE, Jr., Lee-Paritz A, Strunk RC, et al: **Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years: The VDAART Randomized Clinical Trial.** JAMA 2016, **315:**362-370.

Harshfield BJ, McElrath TF,

**101:**394-415.

2018, **103:**2936-2948.

[97] Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, Michigami T, Tiosano D, Mughal MZ, Makitie O, et al: **Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.** J

Szymlek-Gay EA, Murray E, Worsley A, Daly RM: **Associations of Maternal Vitamin D Deficiency with Pregnancy and Neonatal Complications in Developing Countries: A Systematic** 

**40**

Vitamin D deficiency is common in elderly people, especially in patients with comorbidity and polypharmcy. In this group, low vitamin D plasma concentration is related to osteoporosis, osteomalacia, sarcopenia and myalgia. Vitamin D status in geriatric population is an effect of joint interaction of all vitamin D metabolic pathways, aging processes and multimorbidity. Therefore, all factors interfering with individual metabolic stages may affect 25-hydroxyvitamin D plasma concentration. The known factors affecting vitamin D metabolism interfere with cytochrome CYP3A4 activity. The phenomenon of drugs and vitamin D interactions is observed first and foremost in patients with comorbidity. This is a typical example of the situation where a lack of "hard evidence" is not synonymous with the possible lack of adverse effects. Geriatric giants, such as sarcopenia (progressive and generalized loss of skeletal muscle mass and strength) or cognitive decline, strongly influence elderly patients. Sarcopenia is one of the musculoskeletal consequences of hypovitaminosis D. These consequences are related to a higher risk of adverse outcomes, such as fracture, physical disability, a poor quality of life and death. This can lead not only to an increased risk of falls and fractures, but is also one of the main causes of frailty syndrome in the aging population. Generally, Vitamin D plasma concentration is significantly lower in participants with osteoporosis and muscle deterioration. In some observational and uncontrolled treatment studies, vitamin D supplementation led to a reduction of proximal myopathy and muscle pain. The most positive results were found in subjects with severe vitamin D deficiency and in patients avoiding high doses of vitamin D. However, the role of vitamin D in muscle pathologies is not clear and research has provided conflicting results. This is most likely due to the heterogeneity of the subjects, vitamin D doses and environmental factors.

**Keywords:** Vitamin D, pleiotropic effect, elderly, aging

#### **1. Introduction**

Vitamin D is a fat-soluble vitamin mainly produced by the skin after sun exposure (cholecalciferol - vitamin D3) and can also be obtained from food (ergocalciferol-vitamin D2 and vitamin D3) or supplementation. In the liver, vitamin D (the term "vitamin D" refers both vit.D2 and vit.D3") is converted to 25-hydroxyvitamin D [25(OH)D]), also known as "calcidiol", the major circulating metabolite of vitamin D which can be measured in the blood. In the kidney, [25(OH)D] is converted by 1-alfa-hydroxylase into its active form called 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as "calcitriol", that plays a vital role in maintaining bone

homeostasis by regulating calcium metabolism. This action of [1,25(OH)2D] is referred to as endocrine action. The other area where [25(OH)D] is converted by peripheral 1-alfa-hydroxylase to [1,25(OH)2D] are cells in various tissues. There, [1,25(OH)2D] regulation by autocrine or paracrine actions have been observed.

Vitamin D deficiency and insufficiency is one of the major world-wide health problems and its consequences seem to be more serious in the elderly population than in younger adults. It has been associated with a wide range of diseases including autoimmune diseases (among others multiple sclerosis, type 1 diabetes, rheumatoid arthritis), cardiovascular diseases (for example stroke), infectious diseases (bacterial, viral and, fungal), type 2 diabetes and some types of cancers (colorectal, breast and prostate gland). It is also recognized that vitamin D deficiency is associated with some psychiatric disorders including depression, neurocognitive dysfunction and others forms of neurodegenerative disorders (Alzheimer's disease) [1].

This recognition has not only resulted in broadening our knowledge and more conscious vitamin D prescriptions but also led to the crucial question in everyday clinical practice: How can we use our knowledge to improve care for elderly people with vitamin D deficiency and to guide future research studies? Therefore, our publication is focused on distinctive characteristics of vitamin D metabolism, deficiency and drug interaction in the elderly population. As the range of aspects of vitamin D effects in the geriatric population is extremely wide, only chosen elements typical for elderly patients could be presented to emphasise the complexity of the issue.

#### **2. Vitamin D deficiency in the aging population**

Available data indicates that in many countries all over the world, the general population (irrespective of the latitude of residence, age, sex and race) and patients considered as otherwise healthy, suffer from vitamin D insufficiency, defined as 25(OH)D < 30 ng/ml. Recent large observational data have suggested that ~40% of Europeans are vitamin D deficient, and 13% are severely deficient [2]. When 25-hydroxyvitamin D levels were analyzed in relation to age (based on 10-year ranges) there were significant differences in the level of 25(OH)D. The level of 25(OH) D was significantly lower in the older population. However, there are conflicting data concerning the subject, for example in a large Japanese study, the adjusted odds ratio for circulating 25OHD > 75 nmol/l (>30 ng/ml) was in men and women aged >70 years (reference group: individuals aged <50 years) 2.55 and 2.26, respectively. In Bergman et all study, patients aged over 65 years had significant lower circulating 25OHD levels than patients over 75 years [3–6].

#### **3. Elderly people are not a homogenic population**

Meanwhile, the elderly and the oldest-old are one of the fastest growing populations all over the world. The number of people aged 65 and older is expected to rapidly increase in the next decades. Not only the elderly, but also the oldest old are still increasing in numbers. Globally, the current average annual growth rate of people aged 80 years or older (3.8 per cent) is twice as high as the growth rate of the persons younger than 60 years of age (1.9 per cent) [7]. Despite the same range of biological age, it is not a homogenic population regarding the aging type (successful or unsuccessful). Multimorbidity combined with polypharmacy is common, so functional assessment and mobility determine the quality of life. The role of vitamin D in the prevention and treatment of diseases associated with aging

**43**

outcomes.

**5.1 Sarcopenia**

*Vitamin D in Elderly*

*DOI: http://dx.doi.org/10.5772/intechopen.97324*

focus on renal and liver insufficiency.

**5. Vitamin D and geriatric giants**

is still being researched. Therefore, during last decade, geriatric medicine has been focused on studies concerning not only vitamin D deficiency in elderly, but especially on its possible impact on Healthy life years (HLY, also called disability-free life expectancy) taking into account the role of vitamin D considered as a potential factor strongly influencing possible elongation of HLY. Vitamin D status has been widely studied in the last decade. Undoubtedly, one of the most important clinical

question concerns the possibilities of preventing of unhealthy aging.

**4. Factors contributing to vitamin D deficiency in the elderly**

Most importantly, [1,25(OH)2D] directly or indirectly regulates over 200 genes including those involved in: rennin production in the kidney, insulin in the pancreas, the release of cytokines from lymphocytes, production of cathelicidin by macrophages, and the growth and proliferation smooth muscle cells and cardiomyocytes. The main cause of aging-associated vitamin D deficiency is low vitamin D production. As we age, there is a reduction in the skin's concentration of 7-dehydrocholesterol [8]. Specifically, for each decade past the age of 40, there is approximately a 10 to 15% decrease in the level of 7-dehydrocholesterol. Furthermore, the character of dressing style makes the sun exposure indispensable as well as short time of outdoor activities, taking into account that a sufficient amount of sunlight radiation for vitamin D production by the skin only occurs between May and September in some latitudes. Additionally, there is about a 35% decrease in intestinal calcium absorption after the age of 70 [9]. This decrease is even greater in women because of reduced fractional calcium absorption and estrogen changes after the menopause with increased urinary calcium losses [10]. Other causes of aging-associated vitamin D deficiency are related to poor vitamin D and calcium nutrition. With age, comorbidity must also be taken into account with a special

With advanced age, people appear to change their health status perception as a range of independence rather than lack of disease. The presence of "geriatric giants" (coined by Bernard Isaacs in 1965 to encompass common impairments) contributes to more serious consequences than in younger groups [11–13]. Recent epidemiological research has shown that the concentration of 25-hydroxyvitamin D may have an impact on various age-related diseases, as well as on geriatric giants. Geriatric giants are common, have multiple contributing factors and their consequences are stronger in older groups of patients. Some geriatric giants, like sarcopenia, falls or cognitive decline, neurodegenerative disease, and depression are likely to have extremely strong impact on independency of individuals and high risk of negative

Sarcopenia is known as a new geriatric giant. It is an interdisciplinary and multifactor symptom whose prevalence rises with age. Furthermore, the development of secondary hyperparathyroidism favors a negative calcium balance, high bone turnover and accelerates age-related bone loss and osteoporotic fractures.

According to the consensus of The European Working Group on Sarcopenia in Older People, the diagnosis is based on three criteria: low muscle strength or/and

*Vitamin D in Elderly DOI: http://dx.doi.org/10.5772/intechopen.97324*

*Vitamin D*

the issue.

**2. Vitamin D deficiency in the aging population**

lower circulating 25OHD levels than patients over 75 years [3–6].

**3. Elderly people are not a homogenic population**

Available data indicates that in many countries all over the world, the general population (irrespective of the latitude of residence, age, sex and race) and patients considered as otherwise healthy, suffer from vitamin D insufficiency, defined as 25(OH)D < 30 ng/ml. Recent large observational data have suggested that ~40% of Europeans are vitamin D deficient, and 13% are severely deficient [2]. When 25-hydroxyvitamin D levels were analyzed in relation to age (based on 10-year ranges) there were significant differences in the level of 25(OH)D. The level of 25(OH) D was significantly lower in the older population. However, there are conflicting data concerning the subject, for example in a large Japanese study, the adjusted odds ratio for circulating 25OHD > 75 nmol/l (>30 ng/ml) was in men and women aged >70 years (reference group: individuals aged <50 years) 2.55 and 2.26, respectively. In Bergman et all study, patients aged over 65 years had significant

Meanwhile, the elderly and the oldest-old are one of the fastest growing popula-

tions all over the world. The number of people aged 65 and older is expected to rapidly increase in the next decades. Not only the elderly, but also the oldest old are still increasing in numbers. Globally, the current average annual growth rate of people aged 80 years or older (3.8 per cent) is twice as high as the growth rate of the persons younger than 60 years of age (1.9 per cent) [7]. Despite the same range of biological age, it is not a homogenic population regarding the aging type (successful or unsuccessful). Multimorbidity combined with polypharmacy is common, so functional assessment and mobility determine the quality of life. The role of vitamin D in the prevention and treatment of diseases associated with aging

homeostasis by regulating calcium metabolism. This action of [1,25(OH)2D] is referred to as endocrine action. The other area where [25(OH)D] is converted by peripheral 1-alfa-hydroxylase to [1,25(OH)2D] are cells in various tissues. There, [1,25(OH)2D] regulation by autocrine or paracrine actions have been observed. Vitamin D deficiency and insufficiency is one of the major world-wide health problems and its consequences seem to be more serious in the elderly population than in younger adults. It has been associated with a wide range of diseases including autoimmune diseases (among others multiple sclerosis, type 1 diabetes, rheumatoid arthritis), cardiovascular diseases (for example stroke), infectious diseases (bacterial, viral and, fungal), type 2 diabetes and some types of cancers (colorectal, breast and prostate gland). It is also recognized that vitamin D deficiency is associated with some psychiatric disorders including depression, neurocognitive dysfunction and others forms of neurodegenerative disorders (Alzheimer's disease) [1]. This recognition has not only resulted in broadening our knowledge and more conscious vitamin D prescriptions but also led to the crucial question in everyday clinical practice: How can we use our knowledge to improve care for elderly people with vitamin D deficiency and to guide future research studies? Therefore, our publication is focused on distinctive characteristics of vitamin D metabolism, deficiency and drug interaction in the elderly population. As the range of aspects of vitamin D effects in the geriatric population is extremely wide, only chosen elements typical for elderly patients could be presented to emphasise the complexity of

**42**

is still being researched. Therefore, during last decade, geriatric medicine has been focused on studies concerning not only vitamin D deficiency in elderly, but especially on its possible impact on Healthy life years (HLY, also called disability-free life expectancy) taking into account the role of vitamin D considered as a potential factor strongly influencing possible elongation of HLY. Vitamin D status has been widely studied in the last decade. Undoubtedly, one of the most important clinical question concerns the possibilities of preventing of unhealthy aging.

#### **4. Factors contributing to vitamin D deficiency in the elderly**

Most importantly, [1,25(OH)2D] directly or indirectly regulates over 200 genes including those involved in: rennin production in the kidney, insulin in the pancreas, the release of cytokines from lymphocytes, production of cathelicidin by macrophages, and the growth and proliferation smooth muscle cells and cardiomyocytes. The main cause of aging-associated vitamin D deficiency is low vitamin D production. As we age, there is a reduction in the skin's concentration of 7-dehydrocholesterol [8]. Specifically, for each decade past the age of 40, there is approximately a 10 to 15% decrease in the level of 7-dehydrocholesterol. Furthermore, the character of dressing style makes the sun exposure indispensable as well as short time of outdoor activities, taking into account that a sufficient amount of sunlight radiation for vitamin D production by the skin only occurs between May and September in some latitudes. Additionally, there is about a 35% decrease in intestinal calcium absorption after the age of 70 [9]. This decrease is even greater in women because of reduced fractional calcium absorption and estrogen changes after the menopause with increased urinary calcium losses [10]. Other causes of aging-associated vitamin D deficiency are related to poor vitamin D and calcium nutrition. With age, comorbidity must also be taken into account with a special focus on renal and liver insufficiency.

#### **5. Vitamin D and geriatric giants**

With advanced age, people appear to change their health status perception as a range of independence rather than lack of disease. The presence of "geriatric giants" (coined by Bernard Isaacs in 1965 to encompass common impairments) contributes to more serious consequences than in younger groups [11–13]. Recent epidemiological research has shown that the concentration of 25-hydroxyvitamin D may have an impact on various age-related diseases, as well as on geriatric giants. Geriatric giants are common, have multiple contributing factors and their consequences are stronger in older groups of patients. Some geriatric giants, like sarcopenia, falls or cognitive decline, neurodegenerative disease, and depression are likely to have extremely strong impact on independency of individuals and high risk of negative outcomes.

#### **5.1 Sarcopenia**

Sarcopenia is known as a new geriatric giant. It is an interdisciplinary and multifactor symptom whose prevalence rises with age. Furthermore, the development of secondary hyperparathyroidism favors a negative calcium balance, high bone turnover and accelerates age-related bone loss and osteoporotic fractures.

According to the consensus of The European Working Group on Sarcopenia in Older People, the diagnosis is based on three criteria: low muscle strength or/and

low physical performance, and low muscle mass. Sarcopenia is a progressive process and, as a new geriatric giant, has many contributing factors - not only the aging processes, but also vitamin D deficiency, diet, sedentary lifestyle, diseases, drug treatments and drug interactions [14].

Sarcopenia has strong impact on the outcomes of the risk of falls and osteoporotic fractures, lack of independency and lack of ability to perform activities of daily living. Subjects with sarcopenic obesity in the MrOS study had a 1.9 increased risk of any fracture and 3.1 increased risk of spine fracture [15]. The loss of strength is also an important criteria for a diagnosis of frailty syndrome (FS). Therefore, sarcopenia associated with muscle loss in frailty syndrome is one of the major issues of geriatric medicine. The prevalence of frailty syndrome is growing with age. The key role that vitamin D plays in muscle function and low muscle strength has been described in subjects with osteomalacia. The effects of 1,25(OH)D on the proliferation and differentiation in myogenic cells have also been described [20]. Although it remains highly debated, the action of vitamin D via the VDR receptor seems to play a significant role in muscle development and growth [16–18].

It remains unclear in observational studies if there is a key role in vitamin D interaction with muscle, or rather this is the effect of other factors. In an eightyear longitudinal study, the supplementation of vitamin D was not associated with a decreased risk of frailty, but the average daily dosage of oral vitamin D was lower than 400 IU and probably not enough to achieve the target of serum 25(0H) D concentration of 20 ng/ml. Additionally, the lowest 25(OH)D season-specific quartile correlated with a faster rate of muscle strength loss in men aged over 85 [19, 20]. The process was observed in all subjects, including those who were not supplemented with vitamin D. Some interventional studies have been conducted to describe the role of vitamin D in musculosceletal health. However, only a few of these studies had muscle strength as the endpoint. Vitamin D may affect muscle function, particularly in vulnerable populations such as the oldest old and patients with severe sarcopenia. However, it is difficult to create a homogenic group of subjects with the oldest old due to a large number of cofactors that influence physical performance. Nevertheless, vitamin D supplementation for preventing sarcopenia still requires a controlled, double–blind research design.

Sarcopenia being one of the crucial factors of frailty syndrome constitution provides a significant increase in falls that are one of the many causes of disability and functional decline in elderly people. Despite numerous trials and meta-analyses conducted the efficacy of vitamin D supplementation as a mean to prevent falls remains uncertain. The effectiveness of vitamin D in fall prevention remains an issue of the debate. Authors of publications have underscored the importance of further trials on vitamin D and falls and highlight 3 key characteristics these trials should comprise: vitamin D deficiency, vitamin D administration, and unified falls documentation [21].

#### **5.2 Cognitive decline: dementia, depression**

Vitamin D, by direct and indirect regulation of more than 200 genes, exerts bioactivity as a hormone and plays an important role in processes important for the functioning of all systems as well as central nervous system, including calcium absorption, tissue and immune cell growth, and inflammation. However, the crucial role of vitamin D for brain health is supported by the presence of the enzyme that produces its active form 1-hydroxylase in cerebrospinal fluid. The receptor for the active metabolite is found throughout the human brain. Vitamin D has been linked with neuron growth and survival by its regulation of factors such as glutathione, growth factors, neurotrophies and neurotransmitters. Moreover, in animal

**45**

*Vitamin D in Elderly*

*DOI: http://dx.doi.org/10.5772/intechopen.97324*

production and enhanced its removal [22].

*5.2.1 Epidemiological studies*

*5.2.2 Alzheimer's disease (AD)*

**6. Comorbidity and infections**

performance in elderly patients with senile dementia.

until this time, the data of RCT's are not conclusive [23, 24].

models, vitamin D supplementation showed reduced inflammatory biomarkers in the hippocampus. Vitamin D receptor (VDR) seems to be one of the most probable genetic factors of Alzheimer disease (AD). VDR polymorphism increases the risk of AD by 2.3 times and in molecular studies, vitamin D treatment prevented amyloid

The pleiotropic aspects of vitamin D action was tested in numerous observational studies suggesting an association between low serum concentration and the increased risk of other geriatric giants such as cognitive decline, dementia and depression and its supplementation has also shown an improvement in the cognitive

A survey was conducted in Norway among patients over 65 years old with depression who were admitted to psychiatric wards. Vitamin D deficiency (below 20 ng/ml) was observed in 71% patients with depression, 50% patients with bipolar affective disorder and in 25% of control group patients. However, in other studies, there exist a wide range of differences between vitamin D deficiency status (from 34,6% in USA to 100% in British research). Because of the existing conflicts in the data, Li et all in 2018 conducted a meta-analysis to extend the knowledge concerning vitamin D deficiency in patients with depression. They assumed that for every 10 ng/ml of vitamin D level, the increase risk of depression decreases 12%. So, vitamin D supplementation could be useful in the reduction of depression risk, but

Two meta-analysis underscored significantly lower vitamin D concentrations in patients with AD compared to healthy individuals. The risk of AD in patients with vitamin D deficiency was found to be twice higher in an American study and 2.85 times higher in a French study. There exists a correlation between the stage of deficiency and concentration - respectively 19% for concentration below 20 ng/ml and 31% for severe deficiency (<10 ng/ml). However, concentrations >35 ng/ml were not correlated with a of lower risk of AD. Vitamin D pretends to be an independent protective factor reducing Alzheimer diseases processes. For example, in a Spanish study, the dynamics of Alzheimer disease was slower in patients receiving vitamin D. However, the data concerning influence of vitamin D supplementation in AD remains not conclusive [25, 26]. There is also lack of prospective RCT studies.

Notably, several studies have reported an inverse association between 25(OH)D serum levels and the risk of infections (including oral, gastrointestinal, urinary, and respiratory). Many studies underscored the potential immunomodulatory effects as well as the association between the low serum vitamin D levels and many other diseases, such as endocrinal dysfunction leading to increasing insulin resistance, diabetic negative outcomes (for example retinopathy), and cardiovascular disorders. Therefore, all those elements of diseases, typical for elderly patients, create unfavourable background for constitution and progression of geriatric giants. However, in a Lithuanian cross-sectional study (Alekna et al.) of serum 25(OH)D concentrations in relation to activities of daily living (ADL) conducted among octogenarians the regression coefficient for 25(OH)D concentration vs. ADL category

#### *Vitamin D in Elderly DOI: http://dx.doi.org/10.5772/intechopen.97324*

*Vitamin D*

treatments and drug interactions [14].

low physical performance, and low muscle mass. Sarcopenia is a progressive process and, as a new geriatric giant, has many contributing factors - not only the aging processes, but also vitamin D deficiency, diet, sedentary lifestyle, diseases, drug

Sarcopenia has strong impact on the outcomes of the risk of falls and osteoporotic fractures, lack of independency and lack of ability to perform activities of daily living. Subjects with sarcopenic obesity in the MrOS study had a 1.9 increased risk of any fracture and 3.1 increased risk of spine fracture [15]. The loss of strength is also an important criteria for a diagnosis of frailty syndrome (FS). Therefore, sarcopenia associated with muscle loss in frailty syndrome is one of the major issues of geriatric medicine. The prevalence of frailty syndrome is growing with age. The key role that vitamin D plays in muscle function and low muscle strength has been described in subjects with osteomalacia. The effects of 1,25(OH)D on the proliferation and differentiation in myogenic cells have also been described [20]. Although it remains highly debated, the action of vitamin D via the VDR receptor seems to play

It remains unclear in observational studies if there is a key role in vitamin D interaction with muscle, or rather this is the effect of other factors. In an eightyear longitudinal study, the supplementation of vitamin D was not associated with a decreased risk of frailty, but the average daily dosage of oral vitamin D was lower than 400 IU and probably not enough to achieve the target of serum 25(0H) D concentration of 20 ng/ml. Additionally, the lowest 25(OH)D season-specific quartile correlated with a faster rate of muscle strength loss in men aged over 85 [19, 20]. The process was observed in all subjects, including those who were not supplemented with vitamin D. Some interventional studies have been conducted to describe the role of vitamin D in musculosceletal health. However, only a few of these studies had muscle strength as the endpoint. Vitamin D may affect muscle function, particularly in vulnerable populations such as the oldest old and patients with severe sarcopenia. However, it is difficult to create a homogenic group of subjects with the oldest old due to a large number of cofactors that influence physical performance. Nevertheless, vitamin D supplementation for preventing sarcopenia

Sarcopenia being one of the crucial factors of frailty syndrome constitution provides a significant increase in falls that are one of the many causes of disability and functional decline in elderly people. Despite numerous trials and meta-analyses conducted the efficacy of vitamin D supplementation as a mean to prevent falls remains uncertain. The effectiveness of vitamin D in fall prevention remains an issue of the debate. Authors of publications have underscored the importance of further trials on vitamin D and falls and highlight 3 key characteristics these trials should comprise: vitamin D deficiency, vitamin D administration, and unified falls

Vitamin D, by direct and indirect regulation of more than 200 genes, exerts bioactivity as a hormone and plays an important role in processes important for the functioning of all systems as well as central nervous system, including calcium absorption, tissue and immune cell growth, and inflammation. However, the crucial role of vitamin D for brain health is supported by the presence of the enzyme that produces its active form 1-hydroxylase in cerebrospinal fluid. The receptor for the active metabolite is found throughout the human brain. Vitamin D has been linked with neuron growth and survival by its regulation of factors such as glutathione, growth factors, neurotrophies and neurotransmitters. Moreover, in animal

a significant role in muscle development and growth [16–18].

still requires a controlled, double–blind research design.

**5.2 Cognitive decline: dementia, depression**

**44**

documentation [21].

models, vitamin D supplementation showed reduced inflammatory biomarkers in the hippocampus. Vitamin D receptor (VDR) seems to be one of the most probable genetic factors of Alzheimer disease (AD). VDR polymorphism increases the risk of AD by 2.3 times and in molecular studies, vitamin D treatment prevented amyloid production and enhanced its removal [22].

The pleiotropic aspects of vitamin D action was tested in numerous observational studies suggesting an association between low serum concentration and the increased risk of other geriatric giants such as cognitive decline, dementia and depression and its supplementation has also shown an improvement in the cognitive performance in elderly patients with senile dementia.

#### *5.2.1 Epidemiological studies*

A survey was conducted in Norway among patients over 65 years old with depression who were admitted to psychiatric wards. Vitamin D deficiency (below 20 ng/ml) was observed in 71% patients with depression, 50% patients with bipolar affective disorder and in 25% of control group patients. However, in other studies, there exist a wide range of differences between vitamin D deficiency status (from 34,6% in USA to 100% in British research). Because of the existing conflicts in the data, Li et all in 2018 conducted a meta-analysis to extend the knowledge concerning vitamin D deficiency in patients with depression. They assumed that for every 10 ng/ml of vitamin D level, the increase risk of depression decreases 12%. So, vitamin D supplementation could be useful in the reduction of depression risk, but until this time, the data of RCT's are not conclusive [23, 24].

#### *5.2.2 Alzheimer's disease (AD)*

Two meta-analysis underscored significantly lower vitamin D concentrations in patients with AD compared to healthy individuals. The risk of AD in patients with vitamin D deficiency was found to be twice higher in an American study and 2.85 times higher in a French study. There exists a correlation between the stage of deficiency and concentration - respectively 19% for concentration below 20 ng/ml and 31% for severe deficiency (<10 ng/ml). However, concentrations >35 ng/ml were not correlated with a of lower risk of AD. Vitamin D pretends to be an independent protective factor reducing Alzheimer diseases processes. For example, in a Spanish study, the dynamics of Alzheimer disease was slower in patients receiving vitamin D. However, the data concerning influence of vitamin D supplementation in AD remains not conclusive [25, 26]. There is also lack of prospective RCT studies.

#### **6. Comorbidity and infections**

Notably, several studies have reported an inverse association between 25(OH)D serum levels and the risk of infections (including oral, gastrointestinal, urinary, and respiratory). Many studies underscored the potential immunomodulatory effects as well as the association between the low serum vitamin D levels and many other diseases, such as endocrinal dysfunction leading to increasing insulin resistance, diabetic negative outcomes (for example retinopathy), and cardiovascular disorders. Therefore, all those elements of diseases, typical for elderly patients, create unfavourable background for constitution and progression of geriatric giants. However, in a Lithuanian cross-sectional study (Alekna et al.) of serum 25(OH)D concentrations in relation to activities of daily living (ADL) conducted among octogenarians the regression coefficient for 25(OH)D concentration vs. ADL category

was 0.2 (p = 0.01). As highlighted by the authors, it was impossible in this study to determine whether ADL status was a cause or an effect of serum 25(OH)D concentration [27] Complexity of aging processes, age related diseases, geriatric giants and socioeconomic factors influencing elderly patients result in multifactorial, elaborate relation between all this factors to vitamin D status.

The last several months have strongly influenced geriatric medicine. COVID infection has become a clinical example of how important the role of vitamin D is in immunomodulation and anti-inflammatory effect for organisms in particular of aging organs.

#### **7. Vitamin D supplementation and vitamin D treatment in elderly**

#### **7.1 Recommendations for general elderly populations**

Recommendations for vitamin D intake in asymptomatic healthy individuals and in asymptomatic healthy individuals at high risk of vitamin D deficiency (which was published as the Central European Recommendation; similar to the Endocrine Society in USA) are presented in **Tables 1** and **2**. These guidelines recommend the use of vitamin D supplements to obtain and maintain the optimal target 25(OH)D concentration in range of 30-50 ng/ml (75-125 nmol/m).

As presented in **Tables 1** and **2**, people over the age of 65 should take 800- 2000 IU/d of vitamin D throughout the whole year, but people younger than 65 should take vitamin D in the same doses only when the photosynthesis in the skin is insufficient, during the winter months at latitude of >40° , little or no UVB radiation reaches the surface of the earth; such as in Poland from October to March (**Table 1**). The recommended vitamin D intake for groups at risk of vitamin D deficiency and requires larger doses of vitamin D (**Table 2**). This includes night-time workers and dark-skinned people (1000-2000 IU/d of vitamin D for the whole year) and obese people (1600 IU/d to 4000 IU/d for the whole year). There are two essential points about supplementation in the healthy population. First, measurements of [25(OH)D] should not be tested before and during supplementation and second, vitamin D doses larger than the tolerable upper intake levels (ULS) to prevent deficiency of vitamin should not be prescribed. The ULS for adults and seniors with normal body weight is 4000 IU/d, but in obese adults and seniors, it is higher (10 000 IU/d.) [28].

It is very important that treatment of vitamin D deficiency is based on 25(OH) D concentration and antecedent prophylactic management. Individual patients with serum 25(OH) < 20 ng/ml that have clinical risk factors for vitamin D deficiency (decreased intake, gastrointestinal diseases, chronic hepatic diseases, renal diseases, medication with antiepileptic drugs and others which disturbing metabolism of vitamin D) with bone diseases (fragility fractures, documented osteoporosis or


**Table 1.**

*Recommended vitamin D intake in asymptomatic healthy individuals at high risk of vitamin D deficiency.*

**47**

**Figure 1.**

*Vitamin D in Elderly*

Adults Nighttime

workers

Obese (adults and seniors)

toxicity.

**Table 2.**

maintenance.

by a weekly or daily split.

*DOI: http://dx.doi.org/10.5772/intechopen.97324*

high fracture risk, treated with antiresorptive medication, osteomalacia) should be treated. The primary treatment objectives for vitamin D deficiency are the prescription of adequate doses to ensure correction of vitamin D deficiency (>20 ng/ml), reversing the clinical consequences of vitamin D in a timely manner and avoiding

**Season in year October–March April–September October–March April–September**

Dark-skinned — — 1000-20000

**Sufficient skin synthesis Supplementaion vitamin D IU**

— — 1000-2000

— — 1600-4000

Recommendation: do not routinely test 25 (OH)D levels in these groups

The oral route (intake) of treatment is recommended (vitamin D2 and vitamin D3) and should be taken with food to aid absorption. The dosage should be adjusted on the basis of the baseline deficit and the patient's weight (schematic representation for elderly population presented below in the **Figure 1**). The control level of [25(OH)D]

Treatment of vitamin D deficiency should consist of 2 parts: the initial repletion phase of therapy (loading phase), and after the loading phase, initiating the

The loading phase with vitamin D requires 7 to 10 weeks. The aim is to saturate all body compartments so the level of [25(OH)D] is above 30 ng/ml (75 nnom/l. During this time, loading doses of vitamin D (about 300 000 IU) should be given as daily split (divide) doses or intermittent doses every week. Single mega doses (300 000 IU to treat deficiency) are not recommended in the treatment of vitamin D deficiency. Maintenance regiments may be considered after the loading doses.

Example regiments: all loading doses are 300 000 IU and may by administered

*Schematic representation elderly population vulnerable to vitamin D deficiency that defines broad groups for clinical consideration and decision-making about supplementation or treatment with vitamin D elderly* 

*individuals' (PVDD – patients with vitamin D deficiency).*

should be attained during treatment at the beginning and after 7-10 weeks.

*Recommended treatment for individual patients with vitamin D deficiency.*


**Table 2.**

*Vitamin D*

aging organs.

higher (10 000 IU/d.) [28].

after 65 years

was 0.2 (p = 0.01). As highlighted by the authors, it was impossible in this study to determine whether ADL status was a cause or an effect of serum 25(OH)D concentration [27] Complexity of aging processes, age related diseases, geriatric giants and socioeconomic factors influencing elderly patients result in multifactorial, elaborate

The last several months have strongly influenced geriatric medicine. COVID infection has become a clinical example of how important the role of vitamin D is in immunomodulation and anti-inflammatory effect for organisms in particular of

**7. Vitamin D supplementation and vitamin D treatment in elderly**

Recommendations for vitamin D intake in asymptomatic healthy individuals and in asymptomatic healthy individuals at high risk of vitamin D deficiency (which was published as the Central European Recommendation; similar to the Endocrine Society in USA) are presented in **Tables 1** and **2**. These guidelines recommend the use of vitamin D supplements to obtain and maintain the optimal target

relation between all this factors to vitamin D status.

**7.1 Recommendations for general elderly populations**

25(OH)D concentration in range of 30-50 ng/ml (75-125 nmol/m).

skin is insufficient, during the winter months at latitude of >40°

As presented in **Tables 1** and **2**, people over the age of 65 should take 800- 2000 IU/d of vitamin D throughout the whole year, but people younger than 65 should take vitamin D in the same doses only when the photosynthesis in the

radiation reaches the surface of the earth; such as in Poland from October to March (**Table 1**). The recommended vitamin D intake for groups at risk of vitamin D deficiency and requires larger doses of vitamin D (**Table 2**). This includes night-time workers and dark-skinned people (1000-2000 IU/d of vitamin D for the whole year) and obese people (1600 IU/d to 4000 IU/d for the whole year). There are two essential points about supplementation in the healthy population. First, measurements of [25(OH)D] should not be tested before and during supplementation and second, vitamin D doses larger than the tolerable upper intake levels (ULS) to prevent deficiency of vitamin should not be prescribed. The ULS for adults and seniors with normal body weight is 4000 IU/d, but in obese adults and seniors, it is

It is very important that treatment of vitamin D deficiency is based on 25(OH) D concentration and antecedent prophylactic management. Individual patients with serum 25(OH) < 20 ng/ml that have clinical risk factors for vitamin D deficiency (decreased intake, gastrointestinal diseases, chronic hepatic diseases, renal diseases, medication with antiepileptic drugs and others which disturbing metabolism of vitamin D) with bone diseases (fragility fractures, documented osteoporosis or

**Season in year October–March April–September October–March April-September** Adults to 65 years — + 800-2000 —

*Recommended vitamin D intake in asymptomatic healthy individuals at high risk of vitamin D deficiency.*

**Sufficient skin synthesis Supplementaion vitamin D IU**

— — 800-2000

Recommendation: do not routinely test 25 (OH)D levels in these groups

, little or no UVB

**46**

**Table 1.**

*Recommended treatment for individual patients with vitamin D deficiency.*

high fracture risk, treated with antiresorptive medication, osteomalacia) should be treated. The primary treatment objectives for vitamin D deficiency are the prescription of adequate doses to ensure correction of vitamin D deficiency (>20 ng/ml), reversing the clinical consequences of vitamin D in a timely manner and avoiding toxicity.

The oral route (intake) of treatment is recommended (vitamin D2 and vitamin D3) and should be taken with food to aid absorption. The dosage should be adjusted on the basis of the baseline deficit and the patient's weight (schematic representation for elderly population presented below in the **Figure 1**). The control level of [25(OH)D] should be attained during treatment at the beginning and after 7-10 weeks.

Treatment of vitamin D deficiency should consist of 2 parts: the initial repletion phase of therapy (loading phase), and after the loading phase, initiating the maintenance.

The loading phase with vitamin D requires 7 to 10 weeks. The aim is to saturate all body compartments so the level of [25(OH)D] is above 30 ng/ml (75 nnom/l. During this time, loading doses of vitamin D (about 300 000 IU) should be given as daily split (divide) doses or intermittent doses every week. Single mega doses (300 000 IU to treat deficiency) are not recommended in the treatment of vitamin D deficiency. Maintenance regiments may be considered after the loading doses.

Example regiments: all loading doses are 300 000 IU and may by administered by a weekly or daily split.

#### **Figure 1.**

*Schematic representation elderly population vulnerable to vitamin D deficiency that defines broad groups for clinical consideration and decision-making about supplementation or treatment with vitamin D elderly individuals' (PVDD – patients with vitamin D deficiency).*

50 000 IU capsules, one given weekly for 6 weeks.

20 000 IU capsules, two given weekly for 7 weeks.

1000 IU capsules, 4 a day for 10 weeks.

Maintenance regiments after loading doses (given either daily (800 – 4000 IU/D) or intermittently at higher equivalent doses (20 000 every 2 weeks).

The rapid correction of vitamin D deficiency may be necessary in some patients. Rapid correction is required in patients with symptomatic disease or those about to start treatment with potent antiresorptive agent, such as zolenndronate or denosumab. In these cases, the recommended treatment is based on split-loading doses (not single large doses) followed by regular maintenance therapy. Regarding the differences between cholecalciferol and calcifediol, including faster intestine absorption of the calcifediol and linear increment uninfluenced by baseline vitamin D level, in elderly patients often this type of therapy should be considered.

Less urgent correction with lower subsequent dosing is required in patients with increased sensitivity to vitamin D therapy because of genetic abnormality in vitamin D metabolism, co-morbidities such as CD, granulomatoforming diseases or hyperparathyreoidismus [29, 30] .

Analogs 1 alfa (OH)D, 1, alfa 25(0H2)D and others should not be used in therapy of vitamin D deficiency or insufficiency. It is worth of mentioning that in the elderly patients, presence of geriatric giants, multimorbidity and drug interactions should be taken into account.

#### **8. Vitamin D intake and polypharmacy**

The problem of polypharmacy and drug interaction is common in geriatric patients, as multimorbidity is a typical characteristic of this population. This makes it necessary to take into account assumptions concerning the possible interferences of widely used drugs on vitamin D metabolism. Vitamin D status in humans is an effect of the joint interaction of all vitamin D metabolic pathways. Therefore, all factors that interfere with individual metabolic stages may affect 25-hydroxyvitamin D concentration in the circulation. To date, there is little hard evidence that agents such as lipase inhibitors, statins, antimicrobials, antiepileptics and others affect [25(OH)D] concentration in blood serum. The issue of drug and vitamin D interactions is a clear example of a situation where lack of evidence does not equate to "no harm".

The agents with a potential to influence vitamin D status can be roughly divided into drugs that effect vitamin D intestinal absorption and those that influence vitamin D metabolism [31].

Included in the first category, lipase inhibitors are widely used for obesity treatment. They decrease triglycerides hydrolysis in the gut, causing an incremental rise of excreted fat from the typical 5% up to 30%. This increases fat-soluble vitamin D loss in the feces, at the same time decreasing the vitamin D pool available for absorption in the small intestine. In the second category of drugs that influence vitamin D metabolism, statins are an important class and are widely used as very effective agents in both the primary and secondary prevention of cardiovascular diseases.

*Statins* are the most widely prescribed cholesterol-lowering drugs in the world, and they are expected to generate a revenue over \$1 billion by 2025. All statins function as inhibitors of a rate-limiting enzyme in synthesis of cholesterol, namely hydroxyl-methyl coenzyme A (HMG-CoA) reductase. This action brings statins close to vitamin D metabolism, at the same time suggesting their uniform action and similar side effects. Nevertheless, the results of numerous studies show

**49**

*Vitamin D in Elderly*

pathways [32].

the CYP3A4 [33].

*DOI: http://dx.doi.org/10.5772/intechopen.97324*

that the statins/vitamin D interaction give diverse and pleiotropic results. This is evident by a meta-analysis that was "inconclusive on the effects of statins on vitamin D with conflicting directions from interventional and observational studies". Although the fundamental mechanism of action is identical for all the statins, they differ in water solubility, and are catabolized in different ways depending on the statin type, patient's age and vitamin D status, nutritional conditions and insolation. There are two basic ways of the disposition of statins from the human body. One is degradation of some statins in the stomach and excretion as native compounds, the second is an oxidative pathway where the statins undergo modification by a specific cytochrome P450 isoenzymes resulting in an enhanced solubility and subsequent excretion. Some of those enzymes belong to the CYP3A family, and that is the meeting point of the vitamin D and statins catabolic

It is known that atorvastatin, lovastatin and simvastatin are primarily metabolized by CYP3A4, a multi-substrate cytochrome involved also in vitamin D metabolites catabolism. Cytochromes in the CYP3A category are also very important enzymes in the vitamin D catabolic pathways. Therefore, any interference with their activity may cause a disturbance in the vitamin D status of the patient. It is known that some statins may compete for the active centers of the CYP3A enzymes, slowing down the catabolism of the vitamin D metabolites. This results in the vitamin D status increasing, especially in patients who are supplemented with vitamin D. It has been found that atorvastatin treatment significantly increases 25-hydroxyvitamin D concentration in patient's blood serum. This increase is especially visible in patients treated with 800 IU of vitamin D per day. This effect is probably due to inhibitive competition of vitamin D metabolites and the statin for a limited number of active centers available in CYP3A4, and therefore the decrement of the metabolic clearance of the vitamin D metabolites. There are also reports that statins (e.g., rosuvastatin) that are not metabolized by CYP3A4 correlate with the increased 25OHD concentrations in the circulation system of the patient. There is no simple explanation for this finding. One possibility is that statins may act as inducers of the vitamin D 25-hydroxylase activity expressed to a certain extend by

Statins are also known to increase the catabolic clearance of vitamin D metabolites. The mechanism of this phenomenon relays on their affinity for nuclear receptors (PXR, CAR) involved in regulating the expression of CYP3A proteins. [34]. *Antiepileptics (AEDs***)** as carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and valproate have all been associated with bone health problems in epileptic patients. Taking into account that some of them are prescribed as coanalgesics, this type of therapy is widely use in clinical practice among elderly patients. AEDs are known to induce the enzymes from the catabolic pathway of the vitamin D. This action results in a specific sequence of events leading to an increased fracture risk beginning with the induction of hepatic cytochromes and accelerated degradation of the vitamin D metabolites. AEDs can result in decreased vitamin D status and decreased intestinal calcium absorption that has a negative effect on the circulating calcium pool. In turn, this activates a compensatory increase in PTH concentrations resulting in increased bone resorption and an increased risk of fractures. The negative effects of anticonvulsants on fracture risk were confirmed by a population-based analysis. The study had nearly 16,000 participants who had a nontraumatic fracture of the wrist, hip and vertebra with up to 3 matched controls ("n" around 47,000). A significant increase of fracture risk was found for most of the antiepileptic drugs investigated namely for carbamazepine, clonazepam, gabapentin, phenobarbital and phenytoin. OR values ranged from 1,24 for clonazepam to 1,91 for phenytoin. Valproic acid was the only AED

#### *Vitamin D in Elderly DOI: http://dx.doi.org/10.5772/intechopen.97324*

*Vitamin D*

50 000 IU capsules, one given weekly for 6 weeks. 20 000 IU capsules, two given weekly for 7 weeks.

or intermittently at higher equivalent doses (20 000 every 2 weeks).

Maintenance regiments after loading doses (given either daily (800 – 4000 IU/D)

The rapid correction of vitamin D deficiency may be necessary in some patients. Rapid correction is required in patients with symptomatic disease or those about to start treatment with potent antiresorptive agent, such as zolenndronate or denosumab. In these cases, the recommended treatment is based on split-loading doses (not single large doses) followed by regular maintenance therapy. Regarding the differences between cholecalciferol and calcifediol, including faster intestine absorption of the calcifediol and linear increment uninfluenced by baseline vitamin D level, in elderly patients often this type of therapy should be considered. Less urgent correction with lower subsequent dosing is required in patients with increased sensitivity to vitamin D therapy because of genetic abnormality in vitamin D metabolism, co-morbidities such as CD, granulomatoforming diseases or

Analogs 1 alfa (OH)D, 1, alfa 25(0H2)D and others should not be used in therapy of vitamin D deficiency or insufficiency. It is worth of mentioning that in the elderly patients, presence of geriatric giants, multimorbidity and drug interac-

The problem of polypharmacy and drug interaction is common in geriatric patients, as multimorbidity is a typical characteristic of this population. This makes it necessary to take into account assumptions concerning the possible interferences of widely used drugs on vitamin D metabolism. Vitamin D status in humans is an effect of the joint interaction of all vitamin D metabolic pathways. Therefore, all factors that interfere with individual metabolic stages may affect 25-hydroxyvitamin D concentration in the circulation. To date, there is little hard evidence that agents such as lipase inhibitors, statins, antimicrobials, antiepileptics and others affect [25(OH)D] concentration in blood serum. The issue of drug and vitamin D interactions is a clear example of a situation where lack of evidence does not equate

The agents with a potential to influence vitamin D status can be roughly divided

Included in the first category, lipase inhibitors are widely used for obesity treatment. They decrease triglycerides hydrolysis in the gut, causing an incremental rise of excreted fat from the typical 5% up to 30%. This increases fat-soluble vitamin D loss in the feces, at the same time decreasing the vitamin D pool available for absorption in the small intestine. In the second category of drugs that influence vitamin D metabolism, statins are an important class and are widely used as very effective agents in both the primary and secondary prevention of cardiovascular

*Statins* are the most widely prescribed cholesterol-lowering drugs in the world,

and they are expected to generate a revenue over \$1 billion by 2025. All statins function as inhibitors of a rate-limiting enzyme in synthesis of cholesterol, namely hydroxyl-methyl coenzyme A (HMG-CoA) reductase. This action brings statins close to vitamin D metabolism, at the same time suggesting their uniform action and similar side effects. Nevertheless, the results of numerous studies show

into drugs that effect vitamin D intestinal absorption and those that influence

1000 IU capsules, 4 a day for 10 weeks.

hyperparathyreoidismus [29, 30] .

tions should be taken into account.

**8. Vitamin D intake and polypharmacy**

**48**

diseases.

to "no harm".

vitamin D metabolism [31].

that the statins/vitamin D interaction give diverse and pleiotropic results. This is evident by a meta-analysis that was "inconclusive on the effects of statins on vitamin D with conflicting directions from interventional and observational studies". Although the fundamental mechanism of action is identical for all the statins, they differ in water solubility, and are catabolized in different ways depending on the statin type, patient's age and vitamin D status, nutritional conditions and insolation. There are two basic ways of the disposition of statins from the human body. One is degradation of some statins in the stomach and excretion as native compounds, the second is an oxidative pathway where the statins undergo modification by a specific cytochrome P450 isoenzymes resulting in an enhanced solubility and subsequent excretion. Some of those enzymes belong to the CYP3A family, and that is the meeting point of the vitamin D and statins catabolic pathways [32].

It is known that atorvastatin, lovastatin and simvastatin are primarily metabolized by CYP3A4, a multi-substrate cytochrome involved also in vitamin D metabolites catabolism. Cytochromes in the CYP3A category are also very important enzymes in the vitamin D catabolic pathways. Therefore, any interference with their activity may cause a disturbance in the vitamin D status of the patient. It is known that some statins may compete for the active centers of the CYP3A enzymes, slowing down the catabolism of the vitamin D metabolites. This results in the vitamin D status increasing, especially in patients who are supplemented with vitamin D. It has been found that atorvastatin treatment significantly increases 25-hydroxyvitamin D concentration in patient's blood serum. This increase is especially visible in patients treated with 800 IU of vitamin D per day. This effect is probably due to inhibitive competition of vitamin D metabolites and the statin for a limited number of active centers available in CYP3A4, and therefore the decrement of the metabolic clearance of the vitamin D metabolites. There are also reports that statins (e.g., rosuvastatin) that are not metabolized by CYP3A4 correlate with the increased 25OHD concentrations in the circulation system of the patient. There is no simple explanation for this finding. One possibility is that statins may act as inducers of the vitamin D 25-hydroxylase activity expressed to a certain extend by the CYP3A4 [33].

Statins are also known to increase the catabolic clearance of vitamin D metabolites. The mechanism of this phenomenon relays on their affinity for nuclear receptors (PXR, CAR) involved in regulating the expression of CYP3A proteins. [34].

*Antiepileptics (AEDs***)** as carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and valproate have all been associated with bone health problems in epileptic patients. Taking into account that some of them are prescribed as coanalgesics, this type of therapy is widely use in clinical practice among elderly patients. AEDs are known to induce the enzymes from the catabolic pathway of the vitamin D. This action results in a specific sequence of events leading to an increased fracture risk beginning with the induction of hepatic cytochromes and accelerated degradation of the vitamin D metabolites. AEDs can result in decreased vitamin D status and decreased intestinal calcium absorption that has a negative effect on the circulating calcium pool. In turn, this activates a compensatory increase in PTH concentrations resulting in increased bone resorption and an increased risk of fractures. The negative effects of anticonvulsants on fracture risk were confirmed by a population-based analysis. The study had nearly 16,000 participants who had a nontraumatic fracture of the wrist, hip and vertebra with up to 3 matched controls ("n" around 47,000). A significant increase of fracture risk was found for most of the antiepileptic drugs investigated namely for carbamazepine, clonazepam, gabapentin, phenobarbital and phenytoin. OR values ranged from 1,24 for clonazepam to 1,91 for phenytoin. Valproic acid was the only AED

not associated with increased fracture risk. These results are consistent with other population-based studies [35, 36].

Research was conducted to determine if vitamin D supplementation improves the bone condition in patients taking anti-epileptic drugs. The results of a systematic review of 9 studies reported that the research was marred by very little uniformity with respect to the vitamin D dosing regimen, sample sizes, the antiepileptic drugs used, study length and design and bone outcomes measured. Nevertheless, the review states that vitamin D supplementation seems to have a positive effect on bone turnover markers, especially alkaline phosphatase and bone mineralization in adults with epilepsy.

The mechanisms of action and observational data suggest that other factors might interfere with the metabolism of vitamin D. This group comprises of glucocorticoids, immunosuppressive agents (cyclosporine, tacrolimus), many chemotherapeutic agents, highly active antiretroviral agents, and histamine H2-receptor antagonists.

*Glucocorticoids* belong to a widely used class of drugs. Prednisone, hydrocortisone, dexamethasone are used in adrenal replacement, immune suppression and chemotherapy. The well-known side-effect of their application is osteoporosis. Therefore, alterations in vitamin D metabolism have been investigated as a possible mechanism. It has been found that glucocorticoids induce several P450 cytochromes in a way similar to AED, including the vitamin D catabolizing CYP2A4. Although the RCT class studied failed to produce conclusive results, a recent overview of systematic literature revealed that the prevalence range of fractures or osteoporosis in patients taking glucocorticoids is 21 to 30%. The postulated remedy for these problems, save for decreasing the glucocorticoids dose, is vitamin D supplementation [37, 38].

#### **9. Other drugs**

One of published metanalysis underscored undoubted need for further research to understand the impact of drugs that inhibit CYP enzyme activity related to vitamin D status. Regarding such treatment as the antimicrobial agent ketoconazole or proton pump inhibitor omeprazole, have been shown to inhibit both CYP3A4 166, 167 and CYP24 168 in vitro, so far, no studies have evaluated the clinical effect of these drugs on human vitamin D status in elderly [39].

#### **10. Vitamin D toxicity in elderly**

Vitamin D toxicity (VDT) due to excess of vitamin D is a clinical condition characterized by severe hypercalcemia that may persist for a prolonged period of time and lead to serious health consequences. Hypervitaminosis D with hypercalcemia develops after uncontrolled use of vitamin D mega doses or vitamin D metabolites [25(OH)D, 1,25(OH)2D]. Hypervitaminosis D may develop in some clinical conditions as a result of using vitamin D analogs (exogenous VDT). Hypervitaminosis D with hypercalcemia may also be a manifestation of excessive production of 1,25(OH)2D in granulomatous disorders such as sarcoidosis, tuberculosis, leprosy, fungal diseases, giant cell polymyositis, and berylliosis. In healthy geriatric population, exogenous vitamin D toxicity may be caused by prolonged use (months) of vitamin D mega doses, but not by the abnormally high exposure of skin to the sun or by eating a diversified diet. Exogenous VDT due to vitamin D overdosing is diagnosed in the elderly similar as in younger people (very rare) by

**51**

**11. Conclusions**

*Vitamin D in Elderly*

*DOI: http://dx.doi.org/10.5772/intechopen.97324*

concentrations, up to 60 ng/ml (150 nmol/l) [44–47].

The world-wide prevalence of vitamin D deficiency and its role in the maintenance of skeletal and non-skeletal health calls for continuing investigation of vitamin D. These actions should take into account a multitude of confounding variables, including age – elderly as well as the oldest-old, presence of geriatric giants and their consequences, evaluation of vitamin D deficiency as symptomatic or asymptomatic, distinction between the need of supplementation or treatment,

hormone (PTH) activity [40, 41].

markedly elevated 25(OH)D concentrations (>150 ng/ml) accompanied by severe hypercalcemia and hypercalciuria and by very low or undetectable parathyroid

Exogenous VDT can be the result of patients taking excessive amounts of 1,25(OH)2D or other 1–hydroxylated vitamin D analogs [1(OH)D], for example paricalcitol and doxercalciferol, used to treat hypercalcemic disorders, including hypoparathyroidism, pseudohypoparathyroidism, osteomalacia, and end- stage renal failure. When this occurs, hypercalcemia is a harmful side effect of treatment with a pharmacological vitamin D agent that is not related to 25(OH)D concentration and when the concentration value of 1,25(OH)2D is elevated. The increased risk of endogenous VDT is a serious clinical issue in the elderly with granulomaforming disorders and in lymphomas. Patients with granuloma-forming disorders and lymphomas are hypersensitive to vitamin D. Elevated 1,25(OH)2D concentration with hypercalcemia may develop after vitamin D supplementation, from dietary products fortified with vitamin D or after sunbathing. In granulomatous diseases (including tuberculosis, sarcoidosis, leprosy, fungal diseases, infantile subcutaneous fat necrosis, giant cell polymyositis, and berylliosis) endogenous VDT is related to the abnormal extrarenal synthesis of 1,25(OH)2D by activated macrophages. In lymphomas, the etiology of VDT is multiple, heterogeneous, and still not fully recognized. In endogenous VDT, hypercalcemia is related to increased 1,25(OH)2D concentration. In contrast, hypercalcemia is a consequence of high 25(OH)D concentration due to an overdose of vitamin D (exogenous VDT) [42, 43]. Over the last decade, the Institute of Medicine (IOM) and the Endocrine Society have both concluded that acute VDT is extremely rare in the literature, that serum 25(OH)D concentrations must exceed 150 ng/ml (375 nmol/l). Other considerations, such as calcium intake, can have an effect the risk of hypercalcemia and VDT. Despite of the risk factors associated with VDT, there is empirical evidence that vitamin D is among the least toxic fat-soluble vitamins, and significantly less toxic than vitamin A. Dudenkov and colleagues researched more than 20,000 serum 25(OH)D measurements performed at the Mayo Clinic from 2002 to 2011 to determine the prevalence of VDT, demonstrated by the presence of hypercalcemia. The number of individuals with a serum 25(OH)D concentration > 50 ng/ml (>75 nmol/l) had increased by 20 times during that period. On the other hand, high 25(OH)D concentrations can coincide with normal concentrations of serum calcium. In this study, only one patient was diagnosed with hypercalcemia with a 25(OH)D concentration of 364 ng/ml (910 nmol/l). Pietras and colleagues [16] reported no evidence of VDT in healthy adults in a clinical setting who received 50,000 IU of vitamin D2 once every 2 weeks (equivalent to approximately 3,300 IU/day) for up to 6 years. These patients maintained 25(OH) D concentrations of 40–60 ng/ml (100–150 nmol/l). Ekwaru and colleagues had similar findings of no evidence of toxicity in Canadian adults who received up to 20,000 IU of vitamin D3 per day and had a significant increase of 25(OH)D

*Vitamin D*

population-based studies [35, 36].

adults with epilepsy.

supplementation [37, 38].

**9. Other drugs**

antagonists.

not associated with increased fracture risk. These results are consistent with other

Research was conducted to determine if vitamin D supplementation improves the bone condition in patients taking anti-epileptic drugs. The results of a systematic review of 9 studies reported that the research was marred by very little uniformity with respect to the vitamin D dosing regimen, sample sizes, the antiepileptic drugs used, study length and design and bone outcomes measured. Nevertheless, the review states that vitamin D supplementation seems to have a positive effect on bone turnover markers, especially alkaline phosphatase and bone mineralization in

The mechanisms of action and observational data suggest that other factors might interfere with the metabolism of vitamin D. This group comprises of glucocorticoids, immunosuppressive agents (cyclosporine, tacrolimus), many chemotherapeutic agents, highly active antiretroviral agents, and histamine H2-receptor

*Glucocorticoids* belong to a widely used class of drugs. Prednisone, hydrocortisone, dexamethasone are used in adrenal replacement, immune suppression and chemotherapy. The well-known side-effect of their application is osteoporosis. Therefore, alterations in vitamin D metabolism have been investigated as a possible mechanism. It has been found that glucocorticoids induce several P450 cytochromes in a way similar to AED, including the vitamin D catabolizing CYP2A4. Although the RCT class studied failed to produce conclusive results, a recent overview of systematic literature revealed that the prevalence range of fractures or osteoporosis in patients taking glucocorticoids is 21 to 30%. The postulated remedy for these problems, save for decreasing the glucocorticoids dose, is vitamin D

One of published metanalysis underscored undoubted need for further research

to understand the impact of drugs that inhibit CYP enzyme activity related to vitamin D status. Regarding such treatment as the antimicrobial agent ketoconazole or proton pump inhibitor omeprazole, have been shown to inhibit both CYP3A4 166, 167 and CYP24 168 in vitro, so far, no studies have evaluated the clinical effect

Vitamin D toxicity (VDT) due to excess of vitamin D is a clinical condition characterized by severe hypercalcemia that may persist for a prolonged period of time and lead to serious health consequences. Hypervitaminosis D with hypercalcemia develops after uncontrolled use of vitamin D mega doses or vitamin D metabolites [25(OH)D, 1,25(OH)2D]. Hypervitaminosis D may develop in some clinical conditions as a result of using vitamin D analogs (exogenous VDT). Hypervitaminosis D with hypercalcemia may also be a manifestation of excessive production of 1,25(OH)2D in granulomatous disorders such as sarcoidosis, tuberculosis, leprosy, fungal diseases, giant cell polymyositis, and berylliosis. In healthy geriatric population, exogenous vitamin D toxicity may be caused by prolonged use (months) of vitamin D mega doses, but not by the abnormally high exposure of skin to the sun or by eating a diversified diet. Exogenous VDT due to vitamin D overdosing is diagnosed in the elderly similar as in younger people (very rare) by

of these drugs on human vitamin D status in elderly [39].

**10. Vitamin D toxicity in elderly**

**50**

markedly elevated 25(OH)D concentrations (>150 ng/ml) accompanied by severe hypercalcemia and hypercalciuria and by very low or undetectable parathyroid hormone (PTH) activity [40, 41].

Exogenous VDT can be the result of patients taking excessive amounts of 1,25(OH)2D or other 1–hydroxylated vitamin D analogs [1(OH)D], for example paricalcitol and doxercalciferol, used to treat hypercalcemic disorders, including hypoparathyroidism, pseudohypoparathyroidism, osteomalacia, and end- stage renal failure. When this occurs, hypercalcemia is a harmful side effect of treatment with a pharmacological vitamin D agent that is not related to 25(OH)D concentration and when the concentration value of 1,25(OH)2D is elevated. The increased risk of endogenous VDT is a serious clinical issue in the elderly with granulomaforming disorders and in lymphomas. Patients with granuloma-forming disorders and lymphomas are hypersensitive to vitamin D. Elevated 1,25(OH)2D concentration with hypercalcemia may develop after vitamin D supplementation, from dietary products fortified with vitamin D or after sunbathing. In granulomatous diseases (including tuberculosis, sarcoidosis, leprosy, fungal diseases, infantile subcutaneous fat necrosis, giant cell polymyositis, and berylliosis) endogenous VDT is related to the abnormal extrarenal synthesis of 1,25(OH)2D by activated macrophages. In lymphomas, the etiology of VDT is multiple, heterogeneous, and still not fully recognized. In endogenous VDT, hypercalcemia is related to increased 1,25(OH)2D concentration. In contrast, hypercalcemia is a consequence of high 25(OH)D concentration due to an overdose of vitamin D (exogenous VDT) [42, 43].

Over the last decade, the Institute of Medicine (IOM) and the Endocrine Society have both concluded that acute VDT is extremely rare in the literature, that serum 25(OH)D concentrations must exceed 150 ng/ml (375 nmol/l). Other considerations, such as calcium intake, can have an effect the risk of hypercalcemia and VDT. Despite of the risk factors associated with VDT, there is empirical evidence that vitamin D is among the least toxic fat-soluble vitamins, and significantly less toxic than vitamin A. Dudenkov and colleagues researched more than 20,000 serum 25(OH)D measurements performed at the Mayo Clinic from 2002 to 2011 to determine the prevalence of VDT, demonstrated by the presence of hypercalcemia. The number of individuals with a serum 25(OH)D concentration > 50 ng/ml (>75 nmol/l) had increased by 20 times during that period. On the other hand, high 25(OH)D concentrations can coincide with normal concentrations of serum calcium. In this study, only one patient was diagnosed with hypercalcemia with a 25(OH)D concentration of 364 ng/ml (910 nmol/l). Pietras and colleagues [16] reported no evidence of VDT in healthy adults in a clinical setting who received 50,000 IU of vitamin D2 once every 2 weeks (equivalent to approximately 3,300 IU/day) for up to 6 years. These patients maintained 25(OH) D concentrations of 40–60 ng/ml (100–150 nmol/l). Ekwaru and colleagues had similar findings of no evidence of toxicity in Canadian adults who received up to 20,000 IU of vitamin D3 per day and had a significant increase of 25(OH)D concentrations, up to 60 ng/ml (150 nmol/l) [44–47].

#### **11. Conclusions**

The world-wide prevalence of vitamin D deficiency and its role in the maintenance of skeletal and non-skeletal health calls for continuing investigation of vitamin D. These actions should take into account a multitude of confounding variables, including age – elderly as well as the oldest-old, presence of geriatric giants and their consequences, evaluation of vitamin D deficiency as symptomatic or asymptomatic, distinction between the need of supplementation or treatment,

**Figure 2.** *Proposed strategy for geriatric patient with vitamin D deficiency.*

the way of supplementation/treatment, polypharmacy and potential drug interactions. All these factors lead us to define the broad groups for clinical consideration and decision-making regarding the supplementation or treatment with vitamin D in elderly individuals. Heterogeneity of the elderly population contributes to making impossible the creation one, simple algorithm for every patient.

Therefore, the proposed strategy (presented above in the **Figure 2**) to prevent vitamin D deficiency and the negative outcomes in the general elderly population in everyday clinical practice, takes into account multifactorial character of geriatric patient.

### **Author details**

Malgorzata Kupisz-Urbańska1 \*, Jacek Łukaszkiewicz<sup>2</sup> and Ewa Marcinowska-Suchowierska3

1 Department of Geriatrics, Medical Centre for Postgraduate Education, Warsaw, Poland

2 Warsaw Medical School, Poland

3 Department of Gerontology and Geriatrics, School of Public Health, Medical Centre for Postgraduate Education, Warsaw, Poland

\*Address all correspondence to: gosia.kupisz.urbanska@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**53**

phenomenon.

*Vitamin D in Elderly*

**References**

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[1] Pludowski P, Grant WB, Konstantynowicz J, Holick MF. Editorial: Classic and Pleiotropic

Neuwersch-Sommeregger S, Köstenberger M, Tmava Berisha A, Martucci G, Pilz S, Malle O. Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr. 2020 Nov;74(11):1498-1513. doi: 10.1038/ s41430-020-0558-y. Epub 2020 Jan 20.

*DOI: http://dx.doi.org/10.5772/intechopen.97324*

Actions of Vitamin D. Front Endocrinol. 2019 May 29;10:341. doi: 10.3389/

[8] Hilger J, Friedel A, Herr R, et al. A systematic review of vitamin D status in populations worldwide. Br J Nutr. 2014;

[9] Boucher BJ. The Problems of Vitamin D Insufficiency in Older People. Aging

[10] Watson J, Lee M, Garcia-Casal M. Consequences of inadequate intakes of Vitamin A, Vitamin B12, Vitamin D, Calcium, Iron and folate in Older persons. Current geriatric reports. 2018;

[11] Morley JE. A brief history of

geriatrics. J Gerontol A Biol Sci Med Sci.

[12] Morley JE. The new geriatric giants. Clin Geriatr Med. 2017; 33(3): 11-12.

[13] Puvill T, Lindenberg J, Gussekloo J, et al. Associations of various healthratings with geriatric giants, mortality and life satisfaction in older people.

[14] Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Writing Group for the European Working Group on Sarcopenia in Older

Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing.

[15] Harris, R., Strtmayer, E., Boudreau, R., et al. The risk of fracture among men

[16] Tanner SB, Harwell SA. More than healthy bones: a review of vitamin D in muscle health. Ther Adv Musculoskelet

People 2 (EWGSOP2), and the Extended Group for EWGSOP2.

with sarcopenia, obesity, their combination sarcopenic obesity, and men with neither condition: the MrOs Study. 2017 Abstract 1156. ASBMR

Dis. 2015 Aug;7(4):152-9. doi: 10.1177/1759720X15588521.

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Annual Meeting.

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1,25-Dihydroxyvitamin D fluctuations in cardiac surgery are related to age and clinical outcome\*. Crit Care Med. 2012 Jul;40(7):2073-81. doi: 10.1097/

[7] WHO wnday, March 28, 2016 World's older population grows dramatically NIH-funded Census Bureau report offers details of global aging

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Saito T, Kobayashi R, Oshiki R, Watanabe Y, Tsugane S, Sasaki A, Yamazaki O. Impact of demographic, environmental, and lifestyle factors on vitamin D sufficiency in 9084 Japanese adults. Bone. 2015 May;74:10-7. doi: 10.1016/j.bone.2014.12.064. Epub

Apr;103(4):1033-1044.

2015 Jan 7.

### **References**

*Vitamin D*

**52**

**Author details**

Poland

patient.

**Figure 2.**

Malgorzata Kupisz-Urbańska1

and Ewa Marcinowska-Suchowierska3

2 Warsaw Medical School, Poland

Centre for Postgraduate Education, Warsaw, Poland

provided the original work is properly cited.

\*, Jacek Łukaszkiewicz<sup>2</sup>

the way of supplementation/treatment, polypharmacy and potential drug interactions. All these factors lead us to define the broad groups for clinical consideration and decision-making regarding the supplementation or treatment with vitamin D in elderly individuals. Heterogeneity of the elderly population contributes to mak-

Therefore, the proposed strategy (presented above in the **Figure 2**) to prevent vitamin D deficiency and the negative outcomes in the general elderly population in everyday clinical practice, takes into account multifactorial character of geriatric

ing impossible the creation one, simple algorithm for every patient.

*Proposed strategy for geriatric patient with vitamin D deficiency.*

1 Department of Geriatrics, Medical Centre for Postgraduate Education, Warsaw,

3 Department of Gerontology and Geriatrics, School of Public Health, Medical

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: gosia.kupisz.urbanska@gmail.com

[1] Pludowski P, Grant WB, Konstantynowicz J, Holick MF. Editorial: Classic and Pleiotropic Actions of Vitamin D. Front Endocrinol. 2019 May 29;10:341. doi: 10.3389/ fendo.2019.00341.

[2] Amrein K, Scherkl M, Hoffmann M, Neuwersch-Sommeregger S, Köstenberger M, Tmava Berisha A, Martucci G, Pilz S, Malle O. Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr. 2020 Nov;74(11):1498-1513. doi: 10.1038/ s41430-020-0558-y. Epub 2020 Jan 20.

[3] Spiro A, Buttriss JL. Vitamin D:an overview of vitamin D status and intake in Europe. Nutr Bull 2014; 39:322-350.

[4] Cashman KD, Dowling KG, Škrabáková Z, Gonzalez-Gross M, et al. Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr. 2016 Apr;103(4):1033-1044.

[5] Nakamura K, Kitamura K, Takachi R, Saito T, Kobayashi R, Oshiki R, Watanabe Y, Tsugane S, Sasaki A, Yamazaki O. Impact of demographic, environmental, and lifestyle factors on vitamin D sufficiency in 9084 Japanese adults. Bone. 2015 May;74:10-7. doi: 10.1016/j.bone.2014.12.064. Epub 2015 Jan 7.

[6] Börgermann J, Lazouski K, Kuhn J, Dreier J, Schmidt M, Gilis-Januszewski T, Knabbe C, Gummert JF, Zittermann A. 1,25-Dihydroxyvitamin D fluctuations in cardiac surgery are related to age and clinical outcome\*. Crit Care Med. 2012 Jul;40(7):2073-81. doi: 10.1097/ CCM.0b013e31824e8c42.

[7] WHO wnday, March 28, 2016 World's older population grows dramatically NIH-funded Census Bureau report offers details of global aging phenomenon.

[8] Hilger J, Friedel A, Herr R, et al. A systematic review of vitamin D status in populations worldwide. Br J Nutr. 2014; 111: 23-45.

[9] Boucher BJ. The Problems of Vitamin D Insufficiency in Older People. Aging Dis. 2012; 3: 313-329.

[10] Watson J, Lee M, Garcia-Casal M. Consequences of inadequate intakes of Vitamin A, Vitamin B12, Vitamin D, Calcium, Iron and folate in Older persons. Current geriatric reports. 2018; 7: 103-113.

[11] Morley JE. A brief history of geriatrics. J Gerontol A Biol Sci Med Sci. 2004; 59: 1132-1152.

[12] Morley JE. The new geriatric giants. Clin Geriatr Med. 2017; 33(3): 11-12.

[13] Puvill T, Lindenberg J, Gussekloo J, et al. Associations of various healthratings with geriatric giants, mortality and life satisfaction in older people. PLOS One. 2016; 11: 1-13.

[14] Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019 Jan 1;48(1):16-31.

[15] Harris, R., Strtmayer, E., Boudreau, R., et al. The risk of fracture among men with sarcopenia, obesity, their combination sarcopenic obesity, and men with neither condition: the MrOs Study. 2017 Abstract 1156. ASBMR Annual Meeting.

[16] Tanner SB, Harwell SA. More than healthy bones: a review of vitamin D in muscle health. Ther Adv Musculoskelet Dis. 2015 Aug;7(4):152-9. doi: 10.1177/1759720X15588521.

[17] Wagatsuma, A., Sakuma, K. (2014). Vitamin D signaling in myogenesis: potential for treatment for sarcopenia. Bio. Med. Research. International doi: 10.1155/2014/121254

[18] Bo, Y., Liu, C., Ji, Z., Yang, R., An, Q., Zhang, X. et al. (2018). A high whey protein, vitamin D and E supplement preserves muscle mass, strength, and quality of life in sarcopenic older adults: A double-blind randomized controlled trial. Clin Nutr. doi: 10.1016/j. clnu.2017.12.020

[19] Bolzetta, F., Stubbs, B., Noale, M., et al. Low dose vitamin d supplementation and incident frailty in older people: an eight year longitudal study. Exp Gerontol.2018. 101:1-6. doi: 10.1016/j

[20] Granic, A., Hill, T.R, Davis, K., et al. Vitamin D status, Muscle strength and physical performace decline in very old adults: a prospecticve study . Nutrients. 2017. 13;9(4). doi: 10.3390/nu9040379.

[21] Olive Tang, Stephen P. Juraschek, Lawrence J. Appel. Design Features of Randomized Clinical Trials of Vitamin D and Falls: A Systematic Review. Nutrients. 2018 Aug; 10(8): 964. Published online 2018 Jul 26. doi: 10.3390/nu10080964

[22] Pike JW, Meyer MB. The vitamin D receptor: new paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D(3). *Endocrinol Metab Clin North Am*. 2010;39(2):255- 269. doi:10.1016/j.ecl.2010.02.007

[23] Grønli O, Kvamme JM, Jorde R, Wynn R. Vitamin D deficiency is common in psychogeriatric patients, independent of diagnosis. BMC Psychiatry. 2014 May 8; 14(1): 134. doi: 10.1186/1471-244X-14-134.

[24] Lapid MI, Drake MT, Geske JR, Mundis CB, Hegard TL, Kung S, Frye MA. Hypovitaminosis D in

psychogeriatric inpatients. J Nutr Health Aging. 2013 Mar; 17(3): 231-4. doi: 10.1007/s12603-012-0383-7.

[25] Licher, S., de Bruijn, R. F., Wolters, F. J., Zillikens, M. C., Ikram, M. A., & Ikram, M. K. (2017). Vitamin D and the risk of dementia: the Rotterdam study. Journal of Alzheimer's Disease, 60(3), 989-997.

[26] Jayedi, A., Rashidy-Pour, A., & Shab-Bidar, S. (2018). Vitamin d status and risk of dementia and alzheimer's disease: A meta-analysis of doseresponse. Nutritional neuroscience, 1-10.

[27] Pludowski P, Grant WB, Konstantynowicz J and Holick MF (2019) Editorial: Classic and Pleiotropic Actions of Vitamin D. Front. Endocrinol. 10:341. doi: 10.3389/ fendo.2019.00341.

[28] Rusińska A, Płudowski P, Walczak M, Borszewska-Kornacka MK, et al. Vitamin D Supplementation Guidelines for General Population and Groups at Risk of Vitamin D Deficiency in Poland-Recommendations of the Polish Society of Pediatric Endocrino logy and Diabetes and the Expert Panel With Participation of National Specialist Consultants and Representatives of Scientific Societies-2018 Update. Front Endocrinol (Lausanne). 2018 May 31;9:246. doi: 10.3389/fendo.2018.00246.

[29] Holick MF.The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 2017 Jun;18(2):153-165. doi: 10.1007/ s11154-017-9424-1.

[30] Marcinowska-Suchowierska E, Płudowski P. Manegement of osteoporosis in Poland.Calcium and vitamin D, WCO, IFO-ESCEO Congrss, Kraków 19-2204.2018, Lecture, Osteopor.Int. 2018,29. supl.1, Abs. NS74.

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Clin Pract. 2013 Apr;28(2):194-208. doi:

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Endocr Rev. 2016;37(5):521-547.

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1979;64:218-225.

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[34] Bischoff-Ferrari H. A ., Fischer K., Orav E.J., Dawson-Hughes B ., et al. . Statin Use and 25-Hydroxyvitamin D Blood Level Response to Vitamin D Treatment of Older Adults. J Am Geriatr

[35] Arora E., Singh H., Gupta Y.K. Impact of antiepileptic drugs on bone health: Need for monitoring, treatment, and prevention strategies. J. Family Med. Prim. Care. 2016; 5, 248-253.

[36] Jette´N., Lix L.M., Metge C.J., et al. Association of Antiepileptic Drugs With Nontraumatic Fractures A Population-Based Analysis. Arch. Neurol.2011. 68,

[37] Rice B.J., White A.G., Scarpati L.M., Wan G., and Nelson W.W. Long-term Systemic Corticosteroid Exposure: A Systematic Literature Review. Clin.

[38] Kweder H, Housam E.. Vitamin D deficiency in elderly: Risk factors and drugs impact on vitamin D status. Avicenna J Med. 2018 Oct-Dec; 8(4):

[39] Robien K, Oppeneer SJ, Kelly JA, et al. Drug-vitamin D interactions: a systematic review of the literature. Nutr

Ther. 2017; 39, 2216-2229

#### *Vitamin D in Elderly DOI: http://dx.doi.org/10.5772/intechopen.97324*

*Vitamin D*

10.1155/2014/121254

[17] Wagatsuma, A., Sakuma, K. (2014). Vitamin D signaling in myogenesis: potential for treatment for sarcopenia. Bio. Med. Research. International doi:

psychogeriatric inpatients. J Nutr Health Aging. 2013 Mar; 17(3): 231-4. doi:

[25] Licher, S., de Bruijn, R. F., Wolters, F. J., Zillikens, M. C., Ikram, M. A., & Ikram, M. K. (2017). Vitamin D and the risk of dementia: the Rotterdam study. Journal of Alzheimer's Disease, 60(3),

[26] Jayedi, A., Rashidy-Pour, A., & Shab-Bidar, S. (2018). Vitamin d status and risk of dementia and alzheimer's disease: A meta-analysis of dose-

response. Nutritional neuroscience, 1-10.

fendo.2019.00341.

[27] Pludowski P, Grant WB, Konstantynowicz J and Holick MF (2019) Editorial: Classic and Pleiotropic

Actions of Vitamin D. Front. Endocrinol. 10:341. doi: 10.3389/

[28] Rusińska A, Płudowski P,

[29] Holick MF.The vitamin D

s11154-017-9424-1.

Abs. NS74.

deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 2017 Jun;18(2):153-165. doi: 10.1007/

[30] Marcinowska-Suchowierska E, Płudowski P. Manegement of osteoporosis in Poland.Calcium and vitamin D, WCO, IFO-ESCEO Congrss,

Kraków 19-2204.2018, Lecture, Osteopor.Int. 2018,29. supl.1,

Walczak M, Borszewska-Kornacka MK, et al. Vitamin D Supplementation Guidelines for General Population and Groups at Risk of Vitamin D Deficiency in Poland-Recommendations of the Polish Society of Pediatric Endocrino logy and Diabetes and the Expert Panel With Participation of National Specialist Consultants and Representatives of Scientific Societies-2018 Update. Front Endocrinol (Lausanne). 2018 May 31;9:246. doi: 10.3389/fendo.2018.00246.

10.1007/s12603-012-0383-7.

989-997.

[18] Bo, Y., Liu, C., Ji, Z., Yang, R., An, Q., Zhang, X. et al. (2018). A high whey protein, vitamin D and E supplement preserves muscle mass, strength, and quality of life in sarcopenic older adults: A double-blind randomized controlled

[19] Bolzetta, F., Stubbs, B., Noale, M.,

supplementation and incident frailty in older people: an eight year longitudal study. Exp Gerontol.2018. 101:1-6. doi:

[20] Granic, A., Hill, T.R, Davis, K., et al. Vitamin D status, Muscle strength and physical performace decline in very old adults: a prospecticve study . Nutrients. 2017. 13;9(4). doi: 10.3390/nu9040379.

[21] Olive Tang, Stephen P. Juraschek, Lawrence J. Appel. Design Features of Randomized Clinical Trials of Vitamin D and Falls: A Systematic Review. Nutrients. 2018 Aug; 10(8): 964. Published online 2018 Jul 26. doi:

[22] Pike JW, Meyer MB. The vitamin D receptor: new paradigms for the regulation of gene expression by

1,25-dihydroxyvitamin D(3). *Endocrinol Metab Clin North Am*. 2010;39(2):255- 269. doi:10.1016/j.ecl.2010.02.007

[23] Grønli O, Kvamme JM, Jorde R, Wynn R. Vitamin D deficiency is common in psychogeriatric patients, independent of diagnosis. BMC Psychiatry. 2014 May 8; 14(1): 134. doi:

[24] Lapid MI, Drake MT, Geske JR, Mundis CB, Hegard TL, Kung S, Frye MA. Hypovitaminosis D in

10.1186/1471-244X-14-134.

10.3390/nu10080964

trial. Clin Nutr. doi: 10.1016/j.

et al. Low dose vitamin d

clnu.2017.12.020

10.1016/j

**54**

[31] Robien K., Oppeneer S.J., Kelly J.A., Hamilton-Reeves J.M.. Drug–Vitamin D Interactions: A Systematic Review of the Literature. Nutr. Clin. Pract. 2013 28, 194-208.

[32] Mazidi M., Rezaie P., Vatanparast H. and Kengne A.P. Effect of statins on serum vitamin D concentrations: a systematic review and meta-analysis. Eur. J. Clin. Invest. 2017;47, 93-101.

[33] Wang Z., Schuetz E.G., Xu Y., and Thummel K.E. Interplay between Vitamin D and the Drug Metabolizing Enzyme CYP3A4. J. Steroid Biochem. Mol. Biol.2013; 136, 54-58

[34] Bischoff-Ferrari H. A ., Fischer K., Orav E.J., Dawson-Hughes B ., et al. . Statin Use and 25-Hydroxyvitamin D Blood Level Response to Vitamin D Treatment of Older Adults. J Am Geriatr Soc. 2017; 65, 1267-1273.

[35] Arora E., Singh H., Gupta Y.K. Impact of antiepileptic drugs on bone health: Need for monitoring, treatment, and prevention strategies. J. Family Med. Prim. Care. 2016; 5, 248-253.

[36] Jette´N., Lix L.M., Metge C.J., et al. Association of Antiepileptic Drugs With Nontraumatic Fractures A Population-Based Analysis. Arch. Neurol.2011. 68, 107-112.

[37] Rice B.J., White A.G., Scarpati L.M., Wan G., and Nelson W.W. Long-term Systemic Corticosteroid Exposure: A Systematic Literature Review. Clin. Ther. 2017; 39, 2216-2229

[38] Kweder H, Housam E.. Vitamin D deficiency in elderly: Risk factors and drugs impact on vitamin D status. Avicenna J Med. 2018 Oct-Dec; 8(4): 139-146.

[39] Robien K, Oppeneer SJ, Kelly JA, et al. Drug-vitamin D interactions: a systematic review of the literature. Nutr Clin Pract. 2013 Apr;28(2):194-208. doi: 10.1177/0884533612467824.

[40] Tebben PJ, Singh RJ, Kumar R. Vitamin D–Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment. Endocr Rev. 2016;37(5):521-547.

[41] Gupta AK, Jamwal V, Sakul et al. Hypervitaminosis D and systemic manifestations: a comprehensive review. JIMSA. 2014;27(4):236-237.

[42] Mudde AH, van den Berg H, Boshuis PG, et al. Ectopic production of 1,25-dihydroxyvitamin D by B-cell lymphoma as a cause of hypercalcemia. Cancer. 1987;59:1543-1546.

[43] Bell NH, Stern PH, Pantzer E, Sinha TK, DeLuca HF. Evidence that increased circulating 1α, 25-dihydroxyvitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J Clin Invest. 1979;64:218-225.

[44] Dudenkov DV, Yawn BP, Oberhelman SS, et al. Changing incidence of serum 25-hydroxyvitamin D values above 50 ng/ml: a 10-year population-based study.Mayo Clin Proc. 2015;90:577-586.

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Section 2

Vitamin D, Immune System

and Infections

### Section 2
