Drugs affecting calcium levels and bone mineralization
Our discussion of calcium and related drugs has four parts. First, we review calcium physiology. Second, we discuss the syndromes produced by disruption of calcium metabolism. Third, we discuss the pharmacologic agents used to treat calcium-related disorders. And fourth, we consider osteoporosis, the most common calcium-related disorder.
Calcium physiology
Functions, sources, and daily requirements
Functions.
Calcium is critical to the function of the skeletal system, nervous system, muscular system, and cardiovascular system. In the skeletal system, calcium is required for the structural integrity of bone. In the nervous system, calcium helps regulate axonal excitability and transmitter release. In the muscular system, calcium participates in excitation-contraction coupling and contraction itself. In the cardiovascular system, calcium plays a role in myocardial contraction, vascular contraction, and blood coagulation.
Dietary sources.
Dairy products are good sources of calcium. For example, we can get about 300 mg from 1 cup of milk, 8 ounces of yogurt, or 1.5 ounces of cheese. Other good sources include broccoli (180 mg/cup), cooked spinach (240 mg/cup), fortified orange juice (300 mg/8 oz), and fortified cereals (250 to 1000 mg/serving). Information on the calcium content of other foods is available online at www. ucsfhealth.org/education/calcium_content_of_selected_foods/index.html.
Daily requirements.
How much calcium do we need? In 2010, the Institute of Medicine (IOM) of the National Academies issued updated recommendations in a report titled Dietary Reference Intakes for Calcium and Vitamin D. As shown in Table 75–1, adolescents ages 9 through 18 need the most vitamin D: 1300 mg/day. Men and women ages 19 through 50 need 1000 mg/day. After age 50, women should increase their intake to 1200 mg/day, as should men after age 70.
TABLE 75–1
Daily Calcium Intake by Life-Stage Group
Calcium Intake (mg/day) | |||
Life-Stage Group* | AI† | RDA | UL‡ |
0–6 months | 200 | — | 1000 |
6–12 months | 260 | — | 1500 |
1–3 years | — | 700 | 2500 |
4–8 years | — | 1000 | 2500 |
9–18 years | — | 1300 | 3000 |
19–50 years | — | 1000 | 2500 |
51–70 years | |||
Males | — | 1000 | 2000 |
Females | — | 1200 | 2500 |
Over 70 years | — | 1200 | 2000 |
AI = Adequate Intake, RDA = Recommended Dietary Allowance, UL = Tolerable Upper Intake Level.
*All values apply to males and females, except in the 51 to 70 age group. Calcium requirements don’t change during pregnancy or lactation.
†Values for Adequate Intake are derived through experimental or observational data that show a mean calcium intake that appears to sustain a desired indicator of health, such as calcium retention in bone, for most members of the population group. AI values are employed for young children because there are insufficient data to derive an RDA.
‡The Tolerable Upper Intake Level is defined as the maximum intake that is not likely to pose a risk of adverse health effects in almost all healthy individuals in a specified group. The UL is not intended to be a recommended level of intake. There is no established benefit to consuming calcium above the RDA. Data from the Institute of Medicine of the National Academies: Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press, 2010.
Are North Americans taking in enough calcium? According to the IOM report, the answer is Yes: Most of us get sufficient calcium from our diets. However, there is concern that two groups—adolescent girls and postmenopausal women—may not get enough calcium from diet alone, and hence may need calcium supplements. How much supplemental calcium should be taken? Only enough to make up the difference between what the diet provides (about 600 to 900 mg/day) and the recommended dietary allowance (RDA). If dietary calcium plus calcium from supplements exceed the RDA, there is a risk of toxicity: Recent data indicate that taking too much supplemental calcium increases the risk of vascular calcification, myocardial infarction (heart attack), and stroke. In addition, consuming too much calcium can cause kidney stones, which we have known for years.
Body stores
Calcium in bone.
The vast majority of calcium in the body (more than 98%) is present in bone, in the form of hydroxyapatite crystals. It is important to appreciate that bone—and the calcium it contains—is not static. Rather, bone undergoes continuous remodeling, a process in which old bone is resorbed, after which new bone is laid down (Fig. 75–1). The cells that resorb old bone are called osteoclasts and the cells that deposit new bone are called osteoblasts. Both cell types originate in the bone marrow. In adults, about 25% of trabecular bone (the honeycomb-like material in the center of bones) is replaced each year. In contrast, only 3% of cortical bone (the dense material that surrounds trabecular bone) is replaced each year.


Calcium in blood.
The normal value for total serum calcium is 10 mg/dL (2.5 mmol/L, 5 mEq/L). Of this total, about 50% is bound to proteins and other substances, and hence is unavailable for use. The remaining 50% is present as free, ionized calcium—the form that participates in physiologic processes.
Absorption and excretion
Absorption.
Absorption of calcium takes place in the small intestine. Under normal conditions, about one-third of ingested calcium is absorbed. Absorption is increased by parathyroid hormone (PTH) and vitamin D (see below). In contrast, glucocorticoids decrease calcium absorption. Also, a variety of foods (eg, spinach, whole-grain cereals, bran) contain compounds that can interfere with calcium absorption.
Excretion.
Calcium excretion is primarily renal. The amount lost is determined by glomerular filtration and the degree of tubular reabsorption. Excretion can be reduced by PTH, vitamin D, and thiazide diuretics (eg, hydrochlorothiazide). Conversely, excretion can be increased by loop diuretics (eg, furosemide), calcitonin (see below), and loading with sodium. In addition to calcium lost in urine, substantial amounts can be lost in breast milk.
Physiologic regulation of calcium levels
Blood levels of calcium are tightly controlled. Three processes are involved:
Regulation of these processes is under the control of three factors: parathyroid hormone, vitamin D, and calcitonin, as summarized in Table 75–2. You should note that preservation of calcium levels in blood takes priority over preservation of calcium in bone. Hence, if serum calcium is low, calcium will be resorbed from bone and transferred to the blood—even if resorption compromises the structural integrity of bone.
TABLE 75–2
Effects of Parathyroid Hormone, Vitamin D, and Calcitonin on Calcium and Phosphate
PTH | Vitamin D | Calcitonin | |
Calcium | |||
Plasma calcium level | Increase | Increase | Decrease |
Intestinal calcium absorption | Increase | Increase | No effect |
Renal calcium excretion | Decrease | Decrease | Increase |
Calcium resorption from bone | Increase | Increase | Decrease |
Phosphate | |||
Plasma phosphate level | Decrease | Increase |
Parathyroid hormone.
Release of PTH is regulated primarily by calcium, acting through calcium-sensing receptors on cells of the parathyroid gland. When calcium levels are high, activation of the calcium-sensing receptors is increased, causing secretion of PTH to be suppressed. Conversely, when calcium levels are low, receptor activation is reduced, causing PTH release to rise. PTH then restores calcium to normal levels by three mechanisms. Specifically, PTH
• Promotes calcium resorption from bone
• Promotes tubular reabsorption of calcium that had been filtered by the kidney glomerulus
• Promotes activation of vitamin D, and thereby promotes increased absorption of calcium from the intestine
In addition to its effects on calcium, PTH reduces plasma levels of phosphate.
Vitamin D.
Vitamin D is similar to PTH in that both agents increase plasma calcium levels, and they do so by the same mechanisms: (1) increasing calcium resorption from bone, (2) decreasing calcium excretion by the kidney, and (3) increasing calcium absorption from the intestine. Vitamin D differs from PTH in that vitamin D elevates plasma levels of phosphate, whereas PTH reduces levels of phosphate. The actions of vitamin D are discussed further below.
Calcitonin.
Calcitonin, a hormone produced by the thyroid gland, decreases plasma levels of calcium. Hence, calcitonin acts in opposition to PTH and vitamin D. Calcitonin is released from the thyroid gland when calcium levels in blood rise too high. Calcitonin lowers calcium levels by inhibiting the resorption of calcium from bone and increasing calcium excretion by the kidney. Unlike PTH and vitamin D, calcitonin does not influence calcium absorption.
Drugs for disorders involving calcium
Calcium salts
Calcium salts are available in oral and parenteral formulations for treating hypocalcemic states. These salts differ in their percentage of elemental calcium, which must be accounted for when determining dosage.
Oral calcium salts
Therapeutic uses.
Oral calcium preparations are used to treat mild hypocalcemia. In addition, calcium salts are taken as dietary supplements. People who may need supplementary calcium include adolescents, the elderly, and postmenopausal women. As discussed in Chapter 61 (see Box 61–1), calcium supplements may have the added benefit of reducing symptoms of premenstrual syndrome. Also, recent data indicate that calcium supplements can produce a significant, albeit modest, reduction in recurrence of colorectal adenomas.
Adverse effects.
When calcium is taken chronically in high doses (3 to 4 gm/day), hypercalcemia can result. Hypercalcemia is most likely in patients who are also receiving large doses of vitamin D. Signs and symptoms include GI disturbances (nausea, vomiting, constipation), renal dysfunction (polyuria, nephrolithiasis), and CNS effects (lethargy, depression). In addition, hypercalcemia may cause cardiac dysrhythmias and deposition of calcium in soft tissue. Hypercalcemia can be minimized with frequent monitoring of plasma calcium content.
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.
Physiologic actions
Vitamin D is an important regulator of calcium and phosphorus homeostasis. Vitamin D increases blood levels of both elements, primarily by increasing their absorption from the intestine and promoting their resorption from bone. In addition, vitamin D reduces renal excretion of calcium and phosphate (although the quantitative significance of this effect is not clear). With usual doses of vitamin D, there is no net loss of calcium from bone. However, vitamin D can promote bone decalcification if serum calcium concentrations cannot be maintained by increasing intestinal calcium absorption.
Health benefits
Vitamin D is essential for bone health, owing to its effects on calcium utilization. Does vitamin D have other health benefits? Maybe. Maybe not. Studies suggest that vitamin D may protect against diabetes, arthritis, cardiovascular disease, autoimmune disorders, and cancers of the breast, colon, prostate, and ovary. However, according to the IOM report on calcium and vitamin D, the available data are insufficient to support health claims beyond bone health. Hence, until more definitive data are available, the possibility of additional benefits remains open, but not proved.
Sources and daily requirements
Sources.
Vitamin D is obtained through the diet, supplements, and exposure to sunlight. With the exception of shiitake mushrooms and oily fish (eg, salmon, tuna), natural foods have very little vitamin D. Accordingly, dietary vitamin D is obtained mainly through vitamin D–fortified foods, especially cereals, milk, yogurt, margarine, cheese, and orange juice.
Requirements.
In 2010, the IOM issued revised guidelines for vitamin D intake. They now recommend:
• For children under 1 year old, 400 international units (IU)/day
• For all people ages 1 through 70, 600 IU/day
These recommendations are based on the assumption that people get very little of their vitamin D from exposure to sunlight.
According to the IOM report, most people in North America have blood levels of vitamin D in the range needed to support good bone health, and hence do not need vitamin D supplements. Whether taking supplements would confer other benefits remains to be proved.
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:
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).
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.
Actions
Calcitonin has two principal actions: It (1) inhibits the activity of osteoclasts, and thereby decreases bone resorption; and (2) inhibits tubular resorption of calcium, and thereby increases calcium excretion. As a result of decreasing bone turnover, calcitonin decreases alkaline phosphatase in blood and increases hydroxyproline in urine.
Therapeutic uses
Osteoporosis.
Calcitonin-salmon, given by nasal spray or injection, is indicated for treatment of established postmenopausal osteoporosis—but not for prevention. Benefits derive from suppressing bone resorption. The treatment program should include supplemental calcium and adequate intake of vitamin D. Use of calcitonin for osteoporosis is discussed further under Osteoporosis.
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).
TABLE 75–5
Bisphosphonates: Routes and Uses
Major Uses* | ||||||
Drug Name | Route | Osteoporosis in Postmenopausal Women | Osteoporosis in Men | Paget’s Disease of Bone | Hypercalcemia of Malignancy | Glucocorticoid-Induced Bone Loss |
Alendronate [Fosamax] | PO | A | A | A | A | |
Risedronate [Actonel, Atelvia] | PO | A | A | A | A | |
Tiludronate [Skelid] | PO | A | ||||
Ibandronate [Boniva] | PO, IV | A | ||||
Etidronate [Didronel]† | PO, IV | A | I | |||
Zoledronate [Reclast] | IV | A | A | A | A | |
Zoledronate [Zometa]‡ | IV | A | ||||
Pamidronate [Aredia]§ | IV | I | A | A | I |
*A = FDA-approved indication, I = investigational use.
†Also approved for prevention and treatment of heterotropic ossification.
‡Also approved for multiple myeloma and bone metastases from solid tumors.

Stay updated, free articles. Join our Telegram channel

Full access? Get Clinical Tree

