Vitamin D and Calcium and Bioavailability of Calcium in Various Calcium Salts

Abstract

Introduction

The active form of vitamin D, 1,25D3, plays an important function in the metabolism of calcium. The recommended daily INTAKE of Calcium varies from 1300 mg/day during adolescence to 1200 mg/day after the age of 50 years. Similarly, for vitamin D, the recommended daily intake varies from 400 IU/day during adolescence to 1000 IU/day after the age of 70 years. There is an intricate inter-play of homeostasis of calcium led by vitamin D and PTH at various sites like intestine, kidney, and bones. The increased fracture risk due to bone loss and osteoporosis creates a burden on the patient, healthcare provider as well as the health system. As the population grows old worldwide gradually, the long-term sequelae like pain, loss of independence, and institutionalized care will become more pervasive. Behavioral change to incorporate a healthy lifestyle, including optimal calcium and vitamin D intake and physical exercise in adolescence, form the important foundation in the program for osteoporosis prevention.

Conclusion

Increased emphasis on lifestyle modification and nutrition should be given during times of increased bone loss in old age and after menopause.

Background

One of the important minerals present in humans, calcium, influences bone mineralization, contraction of muscle, nerve transmission, blood clotting, and hormone secretion. The primary location of calcium is in the skeletal tissues and serves as the source of various functions that it mediates. It exists in two forms—albumin-bound and ionized and it is the second form that can freely enter a cell and activate the physiological functions. The element is only available to humans by diet and due to reduced dietary intake in the elderly as well as the reduced intestinal absorption along with hormonal decline leads to adverse effects on the skeleton [1]. Vitamin D’s active form, 1,25-dihydroxy vitamin D3 (1,25D3), has an active part in the metabolism of calcium. This chapter shall focus on the regulatory processes involving calcium and vitamin D and its role in the pathogenesis of osteoporosis.

Dietary Sources

Milk products like milk, curd, yogurt, and cheese form the key source of dietary calcium worldwide. 72% of dietary intake of calcium originates from the dairy products with the other minor sources being vegetables, grains, legumes, fruits, and meat products.

The sources of naturally occurring vitamin D for human consumption are limited. Various fish products like fish meat, fish egg, and offal are good sources of vitamin D. Species like eel, pike-porch, herring, and salmon are known sources with vitamin D concentration of 12.4 µg/100 g and above. Other minor sources include egg yolk, tuna, cod, egg, liver, and butter.

Vitamin D2, also known as ergocalciferol and vitamin D3, also known as cholecalciferol, are the biological forms of vitamin D. Ergocalciferol is produced by plants on exposure to ultraviolet light. Vitamin D3 is the biologically active form synthesized in humans and animals on skin exposure to sunlight. Vitamin D3 is more readily absorbed as compared to vitamin D2.

Calcium Absorption

Calcium is absorbed transcellularly by active transport through the mediation of vitamin D receptor (VDR) in the intestinal mucosa. This primarily occurs in the duodenum since it has the highest concentration of VDR. The paracellular uptake which is the passive diffusion between the mucosal cells occurs throughout the intestine and is dependent upon the calcium gradient. The fractional calcium absorption is 25% of the ingested calcium with the rest being excreted through feces (50%) and urine (22%) with minor contributions from sweat, skin, and hair. This rate of absorption is inversely proportional to the quantity of dietary intake. Hence, with reduced dietary intake, the absorption of calcium increases under the homeostatic mechanism influenced by parathormone (PTH) and vitamin D. The fractional calcium absorption is highest in infancy at about 60% attributed primarily to the high lactose content in the diet. It gradually reduces before stabilizing at 25% in young healthy adults. After the age of 40 years, it has been estimated to decline by the rate of approximately 0.21% per year.

Factors Affecting Absorption of Calcium Absorption

The following factors affect the absorption of calcium:

• Phytic acid: Phytic acid which is found in the bran coating of whole grains binds with calcium to make them insoluble. Hence, with a diet which is rich in whole grain products, the calcium absorption shall be reduced.

• Sodium: Sodium acts as a diuretic leading to hypercalciuria and hence reduced absorption.

• Vitamin D: Low intake of vitamin D reduces the absorption of calcium.

• Coffee and tea: Caffeine present in coffees and teas acts as a mild diuretic which leads to excretion of calcium before they can be absorbed.

• Malabsorption syndromes: Diseases like celiac disease and inflammatory bowel disease hamper the absorption of calcium.

Recommended Intake of Calcium and Vitamin D

The advised daily intake of calcium varies from 1300 mg/day during adolescence to 1200 mg/day after the age of 50 years (Table 1). Similarly, for vitamin D, the advised daily intake varies from 200 IU/day during adolescence to 800 IU/day after the age of 70 years. There is no currently any international consensus regarding the ideal dosage range for vitamin D (Table 2).

Table 1.

Recommended dietary intake of calcium

Age	Male (mg)	Female (mg)	Pregnant (mg)	Lactating (mg)
0–6 months*	200	200
7–12 months*	260	260
1–3 years	700	700
4–8 years	1000	1000
9–13 years	1300	1300
14–18 years	1300	1300	1300	1300
19–50 years	1000	1000	1000	1000
51–70 years	1000	1200
> 70 + years	1200	1200

* Signifies / higlights the age below one year

Table 2.

Recommended dietary intake of vitamin D

Age	Male	Female	Pregnancy	Lactation
0–12 months*	10 mcg (400 IU)	10 mcg (400 IU)
1–13 years	15 mcg (600 IU)	15 mcg (600 IU)
14–18 years	15 mcg (600 IU)	15 mcg (600 IU)	15 mcg (600 IU)	15 mcg (600 IU)
19–50 years	15 mcg (600 IU)	15 mcg (600 IU)	15 mcg (600 IU)	15 mcg (600 IU)
51–70 years	15 mcg (600 IU)	15 mcg (600 IU)
> 70 years	20 mcg (800 IU)	20 mcg (800 IU)

* Signifies / higlights the age below one year

Role of Vitamin D and Parathormone in Calcium Metabolism

The two sources of vitamin D are de novo synthesis from 7-dehydrocholestrol in the skin by ultraviolet radiation and from diet by consumption of fish oils and fortified foods. Two hydroxylations, the first at C-25 in the liver and the second at C-1 in the kidney, lead to the active form of vitamin D (1,25D3). The first hydroxylated form is the most common circulating form of vitamin in bloodstream and the most reliable indicator of vitamin body [2]. The main enzyme essential for the first hydroxylation at C-25 has been isolated to be CYP2R1 [3]. Apart from CYP2R1, other 25-hydroxylases also take partS in the C-25 hydroxylation process in the liver. Vitamin-D-binding protein (DBP) transports these products to the kidney where megalin acts as the surface receptor for DBP [4]. The 25-hydroxylated form is converted to 1,25D3 in the proximal tubules by CYP27B1 (25-hydroxy vitamin D 1-alpha hydroxylase), the deficiency of which leads to type 1 vitamin-D-dependent rickets [5]. The enzyme responsible for degradation or inactivation of 1,25D3 is CYP24A1 (25-hydoxy vitamin D 24-hydroxylase) [6]. Hence, in absence or deficiency of CYP24A1, clearance of 1,25D3 shall not be possible [7]. The elevation of PTH due to hypocalcemia results in activation of CYP27B1 and inhibition of CYP24A1. The 1,25D3 formed creates an auto-regulatory feedback loop by suppressing PTH formation, inhibiting CYP27B1, and activating CYP24A1. Vitamin D metabolism is also influenced by FGF23 which suppresses CYP27B1 and induces CYP24A1 which result in reduction of 1,25D3. The functions of vitamin D are genetically influenced through the VDR and retinoid X receptor [8].

The principal function of 1,25D3 is to increase the absorption of calcium from the small and large intestine. It plays an important role in intestinal transcellular calcium transport. It does so by expressing various proteins like apical membrane calcium channel protein (TRPV6), calcium-binding protein (calbindin), plasma membrane CaATPase (PMCA1b), and hence influences the entry, binding as well as extrusion of calcium in the intestinal cells [9]. Animal studies have indicated a synergistic action of TRPV6 and calbindin in the homeostasis of calcium levels [10]. Apart from TRPV6 and calbindin, several other minor proteins are also involved in the calcium transport process in response to 1,25D3 [10].

In the absence of sufficient and adequate vitamin D absorption from the intestine, action is mediated through PTH which increases the reabsorption of calcium from the renal tubules via the action of apical calcium channel protein (TRPV5) and various calbindins as well as the resorption of bone [11]. All the events occurring in the renal tubules are regulated by 1,25D3 [12]. The absence of TRPV5 and various calbindins leads to severe calciuria as well as significant changes in the bone micro- as well as macro-structure. It should be noted that both 1,25D3 as well as PTH stimulate bone resorption so as to maintain adequate serum calcium levels.

Bone Health and Vitamin D

Peak bone mass is achieved by the third decade of life with like genetics and lifestyle factors like physical activity and nutrition influencing it. Osteoporosis which is characterized by reduced bone strength and higher risk of fragility fractures is more common in the postmenopausal women [13]. This increased and accelerated bone loss is attributed to the loss of estrogen [14]. This relationship between loss of estrogen and bone loss has also been observed in males [14]. This process of bone loss is related to the achievement and maintenance of the peak bone bass during adulthood.

The effect of vitamin D and calcium in skeletal health has been explored in randomized studies with a recent meta-analysis reporting reduction of hip fractures by 18% and vertebral fractures by 12% with combined supplementation of calcium and vitamin D [15]. An optimal dose of 800 IU of vitamin D daily\po with serum levels of 29.7 ng/ml of 25D3 was suggested for optimal results [16]. Importantly, two studies in the meta-analysis failed to show any benefits arising out of combined supplementation [17, 18]. This could be attributed to the low compliance rate with the treatment regimen as well as suboptimal daily dosage of vitamin D or calcium or both.

Serum level of 30 ng/ml is considered adequate for 25D3. Risk factors for its reduced levels include increased age, dark skin tone, obesity, and various chronic diseases. An adequate amount of vitamin D (800 IU per day) along with calcium intake (1200–1400 mg per day) leads to 25D3 levels above the range of 30 ng/ml in 97.5% of postmenopausal women [19]. Non-response has been seen with only an increase in 25D3 being noted. The reason being postulated is the DNA methylation levels of the hydroxylases which are high in the non-responders [20].

Muscle Health and Vitamin D

Vitamin D has showed positive effect on muscle power, physical performance, and body sway [21]. Sarcopenia has long been recognized as one of the essential components of age-related decline in musculoskeletal health. The condition is related to low levels of circulation 25D3 [22]. Randomized controlled studies in elder frail women have shown an increase in muscle mass by 10% by administration of high-dose vitamin D [23]. A meta-analysis examining various trials on supplementation strategies showed improvement in power of the muscles in the upper and lower limb [24]. Osteosarcopenic obesity which comprises the concept of frailty, osteoporosis, and sarcopenia affects individuals who are at increased risk of falls and fragility fractures [25]. Vitamin D has the potential to influence all the three domains of sarcopenic obesity by improving muscle mass, bone mass, and insulin sensitivity. Individuals who are elderly with low vitamin D shall benefit from vitamin D supplementation.

What Happens During Aging?

As age progresses, there is reduced calcium absorption from the intestine leading to secondary hyperparathyroidism and bone resorption [1]. This occurs due to the following reasons: (1) decreased expression of TRPV 6, (2) decreased expression of calbindin, (3) increased expression of 24-hydoxylases, and (4) decreased expression of 1-hydroxylases [26]. The combined effect is a reduced calcium absorption in the intestine, reduced formation of 1,25D3, and increased catabolism of 1,25D3. Reports also suggest that there is gradual resistance of the intestinal cells to 1,25D3 [27]. The reduction in the quantity as well as quality of VDR in the intestine has also been suggested [28]. This can be explained due to altered recruitment of VDR by 1,25D3 as age progresses.

Apart from the intestine, age-related changes in kidney also occur which have effects on the calcium homeostasis [29]. The gradual decline of glomerular filtration rate correlates with the reduced serum levels of 1,25D3 [30]. Renal hydroxylation in response to PTH also declines [31]. Along with it, there is reduction in VDR and TRPV5 which reduce the efficiency of reabsorption of calcium in the renal tubules [26].

Hence, to summarize, the following occur in response to aging with respect to metabolism of vitamin D and calcium:

1. Reduced production and conversion to 1,25D3

2. Reduction in dietary vitamin D

3. Reduced renal function

4. Decreased level of VDR

5. Reduced absorption of calcium in the intestine

6. Increased 24-hydroxylation

Vitamin D Analogs

Apart from the numerous options for the pharmacological treatment of osteoporosis, vitamin D analogs have also been studies for their role. Alphacalcidol (1-hydroxy vitamin D3), which gets converted into 1,25D3 in the liver, has been shown to be more efficacious than vitamin D and calcium in improving the bone mineral density (BMD) of lumbar spine [32]. The serum calcium levels stayed within normal limits indicating its safety profile [33].

A newer analog, eldecalcitol (1,25 dihydroxy 2b hydroxypropyloxy), which has been approved for the use in osteoporosis, has lower affinity for VDR but higher affinity for DBP as compared to 1,25D3 [34]. It also has a longer half-life as compared to 1,25D3 [35]. It also has less propensity for catabolism by 24-hydroxylation [36]. Animal studies report its suppressive action on the osteoclasts as well as its anabolic function on bone formation [37]. It is more potent in improving BMD at spine and hip as well as increasing serum calcium levels as compared to alphacalcidol [38]. In a comparative study of eldecalcitol with alendronate and alendronate with vitamin D and calcium, eldecalcitol showed increased reduction of bone turnover markers and improved BMD at the hip [39].

2MD (2-methylene-19-nor(20S)-1,25 dihydroxy vitamin D3) has been reported to increase BMD in the cortical as well as cancellous bone without hypercalcemia in animal studies [40]. However, human studies did not report the positive changes noted in the animal studies [41]. A significant finding, however, was noted. Its potency in suppressing PTH secretion may have a role in renal failure patients.

Calcium Supplementation (Table 3)

Table 3.

Calcium supplements

Preparation	Elemental calcium (%)	Calcium (mg/g)
Calcium carbonate (Shelcal)	40	400
Calcium phosphate (Ostocalcium)	38	383
Calcium citrate (Ucal)	21	210
Calcium acetate (Eliphos®)	25	253
Calcium lactate (Decal)	13	130
Calcium gluconate (Calcium Sandoz)	9	93

Calcium supplementation forms an important component in the treatment of osteoporosis, and numerous formulations of calcium are available for this purpose.

• Calcium carbonate is the commonest formulation available with 40% of elemental calcium. It provides the highest amount of elemental calcium and is usually well-tolerated when consumed with meals. It is one of the cheapest formulations of calcium available. It is the formulation of choice in patients of chronic renal failure due to its good phosphate binding capacity. It should also be borne in mind that it has limited solubility as well as absorption in high gastric pH.

• Calcium citrate malate provides elemental calcium of 26% and bioavailability of above 35% which is the highest among all calcium formulations available. It has better absorption in high gastric pH as compared to calcium carbonate. It is recommended for those on anti-acidity drugs like histamine2 blocker or proton pump inhibitor. For patients suspected with achlorhydria, inflammatory bowel disease, or malabsorption syndromes, it shows better efficacy as compared to calcium carbonate. It also has been recognized as a formulation which does not increase the risk of kidney stones.

• Calcium phosphate provides elemental calcium of up to 38% but it is limited by low solubility and absorption as compared to calcium carbonate.

• Calcium acetate, with an elemental calcium of 25%, is also preferred in patients of chronic renal failure because of its phosphate binding capacity.

• With only 9% of elemental calcium available in calcium gluconate, multiple doses need to be taken to achieve the required amount of daily calcium intake.

• Calcium lactate, with similar solubility and absorption profile of calcium gluconate, has 13% elemental calcium and requires multiple doses to achieve the recommended daily intake.

Among the formulations, calcium carbonate and calcium citrate malate are the common formulations used clinically. The maximum dosage of elemental calcium that can be taken in a single dose is 500 mg or less.

Vitamin D Supplementation

Current recommendations advise the beginning of supplementation with a loading or correctional dose. It consists of 60,000 IU/week of vitamin D₃ for 12 weeks in patients with levels < 20 ng/mL and 60,000 IU/week for 8 weeks in patients with levels between 20 and 30 ng/mL. Alternatively, a single intramuscular injection of 600,000 IU can be given if the levels are below 5 ng/mL or undetectable. Prolonged supplementation should be advised as 60,000 IU/month subsequently. Patients should be reassessed after 3–6 months of supplementation. If a patient’s level remains < 30 ng/mL, dosing interval should be reduced or dosage should be increased to 80,000 or 100,000 IU monthly. If a patient’s level rises above 60 to 80 ng/mL, the researchers recommend lengthening the dosing interval.

Vitamin D Toxicity

Vitamin D toxicity occurs usually due to iatrogenic causes or accidental overdose. Supplements which contain vitamin D are now readily obtainable over-the-counter in the market. These supplements could be outside the purview of various enforcement agencies. Along with it, the lack of public awareness regarding safe dosing has led to unsupervised consumption of these supplements. There are numerous and varied clinical presentations of vitamin D toxicity with hypercalcemia being the basic cause. The presentations can include central nervous system, gastrointestinal, cardiovascular, and renal involvement.

The treatment of vitamin D toxicity can be broadly categorized into (1) stabilization of vital parameters and general supportive treatment, (2) management of hypercalcemia, and (3) reduction strategies to reduce vitamin D levels to normalcy. Consumption of vitamin D and calcium supplements should be halted. Dehydration should be managed by intravenous isotonic saline. This measure also helps in improving the renal calcium clearance. Calcitonin and bisphosphonates are recommended in hypercalcemia above 14 gm/dL. The recommended dosage is:

• Calcitonin at dose of 4 U/kg through intramuscular route can be administered and continued every 12 h up to 48 h.

• Intravenous bisphosphonates can be administered simultaneously. Pamidronate 90 mg over 2 h and zoledronic acid 4 mg over 15 min intravenously are the recommended options.

Hemodialysis due to renal failure or refractory hypercalcemia may be required. Future doses of vitamin D should be monitored and titrated accordingly. Patient education and counseling helps in prevention of unsupervised consumption of vitamin D supplements.

Calcium Toxicity

Calcium toxicity rarely occurs from consumption of calcium-rich foods. The unsupervised usage of calcium supplements is generally associated with calcium toxicity. The typical toxicity state of hypercalcemia is seen with either calcium or vitamin D excess. Relatively higher intakes of vitamin D are required to reach a toxic state as compared to calcium. The resultant hypercalciuria can lead to renal insufficiency as well as calcification of vascular and soft tissue calcification causing nephrocalcinosis and nephrolithiasis. Increased absorption of vitamin D from the intestine as well as renal calcium leak can also lead to hypercalciuria in the absence of hypercalcemia.

The presenting features of calcification of kidney tissues, or nephrocalcinosis, are similar to those of renal dysfunction. The presenting symptoms can be burning and frequent urination, nausea, vomiting, and generalized swelling. The condition may also be associated with renal stones.

Conclusion

The active form of vitamin D, 1,25D3, plays an important function in the metabolism of calcium. The recommended daily intake of calcium varies from 1300 mg/day during adolescence to 1200 mg/day after the age of 50 years. Similarly, for vitamin D, the recommended daily intake varies from 400 IU/day during adolescence to 1000 IU/day after the age of 70 years. There is an intricate inter-play of homeostasis of calcium led by vitamin D and PTH at various sites like intestine, kidney, and bones.

The increased fracture risk due to bone loss and osteoporosis creates a burden on the patient, healthcare provider as well as the health system. As the population grows old worldwide gradually, the long-term sequelae like pain, loss of independence, and institutionalized care will become more pervasive. Behavioral change to incorporate a healthy lifestyle, including optimal calcium and vitamin D intake and physical exercise in adolescence, form the important foundation in the program for osteoporosis prevention. Increased emphasis on lifestyle modification and nutrition should be given during times of increased bone loss in old age and after menopause.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

Not applicable.

Declarations

Conflict of Interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical Standard Statement

This article does not contain any studies with human or animal subjects performed by the any of the authors.

Informed Consent

For this type of study informed consent is not required.