Oral calcium salts

Vitamin D

The term vitamin D refers to two compounds: ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃). Vitamin D₃ is the form of vitamin D produced naturally in humans when our skin is exposed to sunlight. Vitamin D₂ is a form of vitamin D that occurs in plants. Vitamin D₂ is used as a prescription drug and to fortify foods. Both forms are used in over-the-counter supplements. It is important to note that both forms of vitamin D produce nearly identical biologic effects. Therefore, rather than distinguishing between them, we will use the term vitamin D to refer to vitamins D₂ and D₃ collectively.

Vitamin D deficiency

Vitamin D deficiency is defined by a serum concentration of 25-hydroxyvitamin D (25OHD) below 20 ng/mL. (Levels above 20 ng/mL are sufficient to maintain bone health.) In actual practice, the target level of 25OHD is usually 30 to 60 ng/mL.

The classic manifestations of vitamin D deficiency are rickets (in children) and osteomalacia (in adults). Signs and symptoms are described above. Taking vitamin D can completely reverse the symptoms of both conditions, unless permanent deformity has already developed.

How much vitamin D is needed to treat deficiency? In 2011, the Endocrine Society made the following recommendations:

• For children under 1 year old, 2000 IU/day

• For children 1 to 18 years old, 4000 IU/day

• For adults age 19 and older, up to 10,000 IU/day

Much higher doses are needed for patients who are obese, and for those taking glucocorticoids and some other drugs.

Screening for vitamin D deficiency is recommended for patients at risk, including pregnant women, obese people, and people with dark skin (because, compared with light-skinned people, they make less vitamin D in response to sunlight).

Activation of vitamin D

In order to affect calcium and phosphate metabolism, vitamin D must first undergo activation. The extent of activation is carefully regulated, and is determined by calcium availability: When plasma calcium falls, activation of vitamin D is increased. The pathways for activating vitamins D₂ and D₃ are shown in Figure 75–2.

Let’s begin by focusing on vitamin D₃, the natural human vitamin. As shown in Figure 75–2, vitamin D₃ (cholecalciferol) is produced in the skin through the action of sunlight on provitamin D₃ (7-dehydrocholesterol). Neither provitamin D₃ nor vitamin D₃ itself possesses significant biologic activity. In the next reaction, enzymes in the liver convert cholecalciferol into calcifediol, which serves as a transport form of vitamin D₃ and possesses only slight biologic activity. In the final step, calcifediol is converted into the highly active calcitriol. This reaction occurs in the kidney and can be stimulated by (1) PTH, (2) a drop in dietary vitamin D, and (3) a fall in plasma levels of calcium.

Vitamin D₂ is activated by the same enzymes that activate vitamin D₃. As we saw with vitamin D₃, only the last compound in the series (in this case 1,25-dihydroxyergocalciferol) has significant biologic activity.

Pharmacokinetics

As a rule, vitamin D is administered orally and then absorbed from the small intestine. Bile is essential for absorption. In the absence of sufficient bile, IM dosing may be required. In the blood, vitamin D is transported complexed with vitamin D–binding protein. Storage of vitamin D occurs primarily in the liver. As discussed, vitamin D undergoes metabolic activation. Reactions that occur in the liver produce the major transport form of vitamin D. A later reaction (in the kidney) produces the fully active form. Excretion of vitamin D is via the bile. Very little leaves in the urine.

Viewing vitamin D as a hormone

Although referred to as a vitamin, vitamin D has all the characteristics of a hormone. With sufficient exposure to sunlight, the body can manufacture all the vitamin D it needs. Hence, under ideal conditions, external sources of vitamin D appear unnecessary. Following its production in the skin, vitamin D travels to other locations (liver, kidney) for activation. Like other hormones, activated vitamin D then travels to various sites in the body (bone, intestine, kidney) to exert regulatory actions. Also like other hormones, vitamin D undergoes feedback regulation: as plasma levels of calcium fall, activation of vitamin D increases; when plasma levels of calcium return to normal, activation of vitamin D declines.

Toxicity (hypervitaminosis d)

Serious vitamin D toxicity (hypervitaminosis D) can be produced by vitamin D doses that exceed 1000 IU/day (in infants) and 50,000 IU/day (in adults). Poisoning occurs most commonly in children; causes include accidental ingestion by the child and excessive dosing with vitamin D by parents. Doses of potentially toxic magnitude are also encountered clinically. When huge therapeutic doses are used, the margin of safety is small, and patients should be monitored closely for signs of poisoning.

Clinical presentation.

Most signs and symptoms of vitamin D toxicity occur secondary to hypercalcemia. Early responses include weakness, fatigue, nausea, vomiting, and constipation. With persistent hypercalcemia, kidney function is affected, resulting in polyuria, nocturia, and proteinuria. Calcium deposition in soft tissues can damage the heart, blood vessels, and lungs; calcium deposition in the kidneys can cause nephrolithiasis. Very large doses of vitamin D can cause decalcification of bone, resulting in osteoporosis; mobilization of bone calcium can occur despite the presence of high calcium concentrations in blood. In children, vitamin D poisoning can suppress growth for 6 months or longer.

Treatment.

Treatment consists of stopping vitamin D intake, reducing calcium intake, and increasing fluid intake. Glucocorticoids may be given to suppress calcium absorption. If hypercalcemia is severe, renal excretion of calcium can be accelerated using a combination of IV saline and furosemide (a diuretic).

Therapeutic uses

The primary indications for vitamin D are nutritional rickets, osteomalacia, and hypoparathyroidism. Other applications include vitamin D–resistant rickets, vitamin D–dependent rickets, and renal osteodystrophy.

Preparations, dosage, and administration

There are six preparations of vitamin D. Four of these—ergocalciferol, cholecalciferol, calcifediol, and calcitriol—are identical to forms of vitamin D that occur naturally. The other two—paricalcitol and doxercalciferol—are synthetic derivatives of natural vitamin D. (The naturally occurring preparations are highlighted in green boxes in Fig. 75–2.) Individual vitamin D preparations differ in their clinical applications (see below).

Two forms of vitamin D—vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol)—are used routinely as dietary supplements. Of the two, vitamin D₃ is preferred. Why? Because vitamin D₃ is more effective than vitamin D₂ at raising blood levels of 25OHD, the active form of vitamin D in the body.

Vitamin D is almost always administered by mouth. One product—calcitriol—can also be given IV. Dosage is usually prescribed in international units. (One IU is equivalent to the biologic activity in 0.025 mcg of vitamin D₃.) Daily dosages of vitamin D range from 400 IU (for dietary supplementation) to as high as 500,000 IU (for vitamin D–resistant rickets).

Ergocalciferol (vitamin D₂).

Ergocalciferol [Calciferol Drops, Drisdol] is approved for hypoparathyroidism, vitamin D–resistant rickets, and familial hypophosphatemia. Ergocalciferol is supplied in capsules (50,000 IU) and an oral solution (8000 IU/mL). The dosage for vitamin D–resistant rickets ranges from 12,000 to 500,000 IU daily. The dosage for hypoparathyroidism ranges from 50,000 to 200,000 IU daily (together with 4 gm of calcium lactate 6 times/day).

Cholecalciferol (vitamin D₃).

Vitamin D₃ [Delta-D] is given as a dietary supplement and for prophylaxis and treatment of vitamin D deficiency. Compared with ergocalciferol (vitamin D₂), cholecalciferol (vitamin D₃) is more effective at raising blood levels of vitamin D. Cholecalciferol is available in tablets containing 400 and 1000 IU.

Calcifediol (25-hydroxy-d₃).

Calcifediol [Calderol] is indicated for the management of metabolic bone disease and hypocalcemia in patients undergoing chronic renal dialysis. Calcifediol is available in capsules (20 and 50 mcg) for oral use. The initial dosage is 300 to 350 mcg/wk (administered in divided doses on a daily or every-other-day schedule). For maintenance, daily doses of 50 to 100 mcg are usually adequate.

Calcitriol (1,25-dihydroxy-d₃).

Calcitriol [Rocaltrol, Calcijex] is indicated for treatment of hypoparathyroidism and management of hypocalcemia in patients undergoing chronic renal dialysis. The drug is supplied in capsules (0.25 and 0.5 mcg), oral solution (1 mcg/mL), and solution for injection (1 and 2 mcg/mL). For dialysis patients, daily doses of 0.5 to 1 mcg are usually adequate. The initial dosage for hypoparathyroidism is 0.25 mcg/day.

Doxercalciferol.

Doxercalciferol [Hectorol] is indicated for prevention and treatment of secondary hyperparathyroidism in patients undergoing chronic renal dialysis. The drug is available in capsules (2.5 and 5 mcg) for oral dosing, and solution (2 mcg/mL) for IV dosing. Dosage must be carefully tailored to the patient. With oral administration, treatment begins with 10 mcg 3 times weekly administered at dialysis; dosage may be gradually increased to a maximum of 20 mcg 3 times a week. With IV administration, treatment begins with a 4-mcg IV bolus 3 times weekly at the end of each dialysis session.

Paricalcitol.

Like doxercalciferol, paricalcitol [Zemplar] is indicated for prevention and treatment of secondary hyperparathyroidism in patients undergoing chronic renal dialysis. The drug is available in capsules (1, 2, and 4 mcg) for oral dosing, and in solution (5 mcg/mL) for dosing by IV bolus. With oral administration, two schedules may be used: (1) once daily and (2) 3 times a week. Treatment begins at 1 to 2 mcg/dose (with the once-daily schedule) or 2 to 4 mcg/dose (with the 3-times-weekly schedule). With IV administration, treatment begins with 0.04 to 0.1 mcg/kg given any time during dialysis—but no more frequently than every other day. Dosage may be gradually increased every 2 to 4 weeks. Doses as high as 0.24 mcg/kg have been used safely.

Calcitonin-salmon

Calcitonin-salmon [Miacalcin, Fortical], a form of calcitonin derived from salmon, is similar in structure to calcitonin synthesized by the human thyroid. Salmon calcitonin produces the same metabolic effects as human calcitonin but has a longer half-life and greater milligram potency. The drug is usually given by nasal spray, but can also be given by injection. Both routes are extremely safe.

Bisphosphonates

Bisphosphonates are structural analogs of pyrophosphate (Fig. 75–3), a normal constituent of bone. These drugs undergo incorporation into bone, and then inhibit bone resorption by decreasing the activity of osteoclasts. Principal indications are postmenopausal osteoporosis, osteoporosis in men, glucocorticoid-induced osteoporosis, Paget’s disease of bone, and hypercalcemia of malignancy. Bisphosphonates may also help prevent and treat bone metastases in patients with cancer (see Chapter 103). Although these drugs are generally very safe, serious adverse effects can occur, including ocular inflammation, osteonecrosis of the jaw, atypical femur fractures, and atrial fibrillation (primarily with IV zoledronate).

Bisphosphonates differ with respect to indications, routes, and dosing schedules. As indicated in Table 75–5, some bisphosphonates are given PO, some are given IV, and some are given by both routes. With oral dosing, absorption from the GI tract is extremely poor. Dosing schedules vary from as often as once a day (with oral agents) to as seldom as once every 2 years (with IV zoledronate).