AHFS Class:

• Replacement Preparations 40:12

Generic Name(s):

• Calcium Acetate

• Calcium Carbonate, Precipitated

• Calcium Chloride

• Calcium Citrate

• Calcium Gluceptate

• Calcium Gluconate

• Calcium Glycerophosphate

• Calcium Lactate

• Calcium Phosphate, Dibasic

Calcium salts are used as a source of calcium, an essential nutrient cation.

Calcium salts are used as a source of calcium cation for the treatment or prevention of calcium depletion in patients in whom dietary measures are inadequate. Conditions that may be associated with calcium deficiency include hypoparathyroidism, achlorhydria, chronic diarrhea, vitamin D deficiency, steatorrhea, sprue, pregnancy and lactation, menopause, pancreatitis, renal failure, alkalosis, and hyperphosphatemia. Administration of certain drugs (e.g., some diuretics, anticonvulsants) may sometimes result in hypocalcemia which may warrant calcium replacement therapy. Calcium should be administered in long-term electrolyte replacement regimens and is also recommended for the routine prophylaxis of hypocalcemia during transfusions with citrated blood. Administration of calcium salts should not preclude the use of other measures intended to correct the underlying cause of calcium depletion.

Dietary Requirements

Since 1941, the Institute of Medicine's (IOM) Food and Nutrition Board of the National Academy of Sciences (NAS) has developed guidelines for adequate dietary intake of essential nutrients.112,153 Nutrient recommendations are issued through Dietary Reference Intakes (DRIs), which are a set of reference values that can be used for planning and assessing diets for healthy populations and for many other purposes.153 DRIs for calcium include the Estimated Average Requirement (EAR), Recommended Dietary Allowance (RDA), Adequate Intake (AI), and Tolerable Upper Intake Level (UL).153 DRIs apply to the healthy general population and consider nutrient levels needed to prevent deficiency as well as those associated with disease risk reduction.112,153 The current methods for establishing DRIs differ from those used in the past and incorporate increased understanding of both population and individual nutrient needs.112,153 The EAR is the nutrient intake value that is estimated to meet the nutrient needs of 50% of individuals in a particular life-stage and gender group.153 The RDA, which is derived from the EAR, currently is defined as the estimated daily dietary intake level that is sufficient to meet the nutrient requirements of 97.5% of the population's requirements.153 The RDA for a given nutrient, in a prescriptive sense, is the goal for dietary intake in individuals.112 If data are insufficient to establish an RDA for a given life-stage group, the AI may be used instead.112 AIs are based on observed or experimentally determined approximations of the average nutrient intake, by a defined population or subgroup, that appears to sustain a defined nutritional state (e.g., usual circulating nutrient levels, nutrient levels for normal growth).112

The previous NAS report from 1997 was unable to establish EARs and RDAs for calcium because of inadequate data attributed in part to uncertainties in the methods used in calcium balance studies, the lack of concordance between observational and experimental data, and the lack of longitudinal data to verify the association between calcium intake, calcium retention, and bone loss.112,153 Since then, emerging data from large-scale randomized controlled studies and more recent calcium balance studies have allowed for estimation of EARs and RDAs in all life stage groups except for infants.153

The principal goal of maintaining an adequate intake of calcium in the US and Canada is to support the development and preservation of bone mass at a level sufficient to prevent fractures associated with osteopenia or osteoporosis in later life and of other calcified tissues (e.g., teeth), although other biologic roles for calcium and related nutrients (e.g., fluoride, magnesium, phosphorus) have been considered in establishing DRIs.112,126,129,147,153 Lifelong intake of adequate calcium is necessary for good bone health at any age.147,148 Although some evidence indicates an inverse relationship between calcium intake and blood pressure101,102,103,115,120,121 and that increased calcium intake can reduce blood pressure in certain healthy individuals and some hypertensive patients,103,104,105,106,115,120,121 there currently is no rationale for recommending calcium supplementation solely to reduce blood pressure; the importance of maintaining adequate calcium intake should be emphasized though, since potential secondary benefits on blood pressure may result.120,121

Adequate intakes of calcium can be accomplished through changes in food consumption behaviors, consumption of nutrient-fortified foodstuffs, use of dietary supplements, or a combination of these.112,147,153 In the US and Canada, calcium principally is obtained from dairy products.112 Other principal sources include fruits, vegetables, and grain products.112,147 In addition, many healthy individuals take dietary supplements containing calcium.112

For specific information on currently recommended dietary reference intakes for calcium, see Dosage and Administration: Dosage.

Parenteral Preparations

Calcium salts are administered IV to treat acute hypocalcemic tetany secondary to renal failure, hypoparathyroidism, premature delivery, and/or maternal diabetes mellitus in infants, and poisoning with magnesium, oxalic acid, radiophosphorus, carbon tetrachloride, fluoride, phosphate, strontium, or radium. Some experts state that administration of calcium also may be useful in the treatment of β-adrenergic blocking agent toxicity in patients with shock refractory to other treatment measures.196

IV calcium gluconate is considered by most clinicians to be the salt of choice for the treatment of acute hypocalcemia. In some situations (e.g., critically ill children with hypocalcemia), calcium chloride may be preferred because it can provide a greater increase in ionized calcium concentrations.403 Some clinicians believe that calcium chloride is the calcium salt of choice for the prevention of hypocalcemia during transfusions with citrated blood. In addition to being irritating, however, the chloride salt is acidifying and generally should not be used when acidosis coincides with hypocalcemia (e.g., renal failure).

Calcium salts have been used IV as adjunctive therapy to reduce spasms in renal†, biliary†, intestinal†, or lead colic. Calcium salts also have been used IV as adjuncts to relieve muscle cramps in the treatment of insect bites or stings (e.g., black widow spider) or to decrease capillary permeability in sensitivity reactions characterized by urticaria or angioedema† and in allergic conditions, including nonthrombocytopenic purpura, dermatitis herpetiformis, drug-induced pruritus, hay fever†, and asthma†.

The calcium glycerophosphate and calcium lactate fixed-combination injection is used IM to increase serum calcium concentrations.142

Calcium infusions (“calcium challenge”) are used to diagnose the Zollinger-Ellison syndrome† and medullary thyroid carcinoma†. In addition, calcium salt injections are used to antagonize neuromuscular blockade† resulting from the use of aminoglycoside antibiotics (e.g., gentamicin, kanamycin, neomycin) with or without agents possessing neuromuscular blocking properties (e.g., gallamine triethiodide).

Advanced Cardiovascular Life Support

Because of the lack of demonstrated benefit and potential for detrimental effects, the American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care currently state that calcium should not be used routinely for advanced cardiovascular life support (ACLS) during cardiac arrest in adults and pediatric patients unless there is documented hypocalcemia, calcium-channel blocker toxicity, hypermagnesemia, or hyperkalemia.196,400,401,403 When used in this setting, experts state that either calcium chloride or calcium gluconate may be administered.403

Oral Preparations

Oral calcium therapy may be used for the treatment of osteoporosis, osteomalacia, chronic hypoparathyroidism, rickets, latent tetany, and hypocalcemia secondary to the administration of anticonvulsant drugs. Calcium salts are also used orally in the adjunctive treatment of myasthenia gravis and the Eaton-Lambert syndrome, and as supplemental therapy for pregnant, postmenopausal, or nursing women. In general, any of the oral calcium salts may be used for chronic replacement therapy.

Although some evidence from early trials suggested a beneficial effect of calcium supplementation on preeclampsia,117,118,125 a more recent, large, well-designed study did not confirm a beneficial effect of calcium supplementation in preventing preeclampsia during pregnancy.117,118 In this study, supplemental administration of calcium (2 g of elemental calcium daily) beginning during the 13th-21st week and continued for the remainder of pregnancy did not prevent preeclampsia, pregnancy-associated hypertension, or adverse perinatal outcomes in healthy nulliparous women.117 However, these findings do not obviate adequate dietary calcium intake during pregnancy nor do they address whether adequate or increased calcium intake can affect blood pressure favorably in pregnant women.105,118,125

Calcium acetate or carbonate is considered to be the salt of choice in patients with chronic renal failure.113,126 In addition to providing a source of calcium, calcium acetate or carbonate sequesters phosphate in the intestine by forming insoluble phosphates that are excreted fecally, thus reducing serum phosphate concentrations and secondary hyperparathyroidism; calcium carbonate also partially corrects metabolic acidosis which may occur in patients with chronic renal failure. Because of the risk of aluminum accumulation and resultant neurotoxic and osteomalacic effects, most clinicians no longer use aluminum hydroxide to inhibit phosphorus absorption; instead calcium acetate or carbonate and/or non-calcium-, non-aluminum-, non-magnesium-containing phosphate binders (e.g., lanthanum carbonate, sevelamer hydrochloride) currently are used.127,130,131,132 Therapeutic measures to control hyperphosphatemia in patients with chronic renal disease include reduction in dietary intake of phosphates, inhibition of intestinal phosphate absorption, and removal via dialysis.113,127,130 In individuals with moderate to severe renal impairment (i.e., glomerular filtration rate of 15-59 mL/minute per 1.73 m²), calcium carbonate or acetate may be used to sequester phosphates in the intestine if serum phosphorus or parathyroid hormone (PTH) concentrations are not controlled through dietary restrictions and/or vitamin D therapy.130 In patients with chronic renal failure, reductions in serum phosphate through dietary restrictions and dialysis generally are insufficient, and inhibition of intestinal phosphate absorption usually is necessary.113,127 In these individuals, either a calcium-containing phosphate binder or a non-calcium-, non-aluminum-, non-magnesium-containing phosphate binder may be used as primary therapy.130,131,132 Some experts state that dialysis patients who remain hyperphosphatemic despite treatment with either calcium-based phosphate binders or non-calcium-, non-aluminum-, non-magnesium-containing phosphate binders should receive both types of phosphate binders in combination.130 Non-calcium-containing phosphate binders are preferred in dialysis patients with severe vascular and/or other soft-tissue calcification.130 Calcium-containing phosphate binders should not be used in dialysis patients who are hypercalcemic or whose plasma PTH concentrations are less than 150 pg/mL on 2 consecutive measurements.130 Use of aluminum-containing phosphate binders should be limited to short periods of time (e.g., a single 4-week course) in patients with difficult-to-control serum phosphorus concentrations (e.g., concentrations exceeding 7 mg/dL).130,133

When taken with meals, calcium acetate or carbonate can contribute to controlling hyperphosphatemia in patients with chronic renal failure by binding to and inhibiting absorption of phosphates in the GI tract.113,127 Caution should be observed in patients undergoing chronic hemodialysis to prevent hypophosphatemia. Patients with end-stage renal failure may develop hypercalcemia when calcium is administered with meals; therefore, other calcium supplementation should not be given concomitantly when calcium salts are used to control hyperphosphatemia in such patients.113 Progressive hypercalcemia secondary to overdose of calcium salts in patients with chronic renal disease can occur and may require emergency treatment measures.113 Chronic hypercalcemia also may lead to vascular and other soft-tissue calcification.113,126 Therefore, periodic (e.g., twice weekly) monitoring of calcium concentrations is recommended during the initial dose adjustment period in patients with chronic renal failure.113 One manufacturer recommends that the serum calcium times phosphate (Ca×P) product should not exceed 66.113 Radiographic evaluation of a suspected anatomic region for early soft-tissue calcification may be useful.113

Vitamin D analogs may be administered concomitantly with oral calcium salts for the treatment of chronic hypocalcemia, especially when caused by vitamin D deficiency.

Calcium chloride, an acid-forming salt, has been used to promote diuresis but, because it is irritating and loses effectiveness after a few days, it is rarely used for this effect.

For the use of calcium carbonate as an antacid, see Antacids 56:04.

Osteoporosis

Calcium salts (e.g., calcium carbonate, calcium citrate) are used as supplements for the prevention and treatment of osteoporosis in patients whose dietary intake of calcium is insufficient.147,148

A principal long-term consequence of inadequate calcium intake is osteoporosis, which is characterized by reduced bone mass, increased bone fragility, and increased fracture risk.100,112,126 Reduced absorption of calcium causes declines in circulating ionized calcium concentrations, which induce increased parathyroid hormone (PTH) synthesis and release.112 PTH then acts to restore circulating calcium concentrations to normal levels by promoting the reabsorption of calcium in the distal renal tubule, by indirectly increasing intestinal absorption secondary to stimulation of activated vitamin D synthesis, and by inducing bone resorption.112 Thus, while circulating calcium concentrations can be maintained at normal levels during calcium deprivation, it is at the expense of skeletal mass.112

Adequate intake of calcium and vitamin D (which increases absorption of calcium) is universally recommended for all individuals to diminish age-related bone loss and prevent osteoporosis.147,148 Controlled clinical studies have demonstrated that the combination of calcium and vitamin D can reduce fracture risk.147,148 In addition to lifestyle modifications (e.g., regular weight-bearing exercise, avoidance of excessive alcohol and tobacco use), the National Osteoporosis Foundation recommends a calcium intake of 1 g daily in men 50-70 years of age, and an intake of 1.2 g daily in women 51 years of age or older and men 71 years of age or older.147 There is no evidence to suggest that increasing intake above these amounts will provide any additional benefit on bone strength; excess calcium intake has been linked to increased risks of kidney stones, cardiovascular disease, and stroke.147 It is important to also ensure sufficient calcium and vitamin D intake in children and younger adults to prevent the development of osteoporosis.148 (See Uses: Dietary Requirements.) If adequate calcium cannot be obtained from diet, calcium supplements are recommended.147

Glucocorticoid-induced Osteoporosis

The American College of Rheumatology (ACR) recommends optimizing dietary intake of calcium (1-1.2 g daily) and vitamin D (600-800 units daily) for the prevention of glucocorticoid-induced osteoporosis in all patients receiving long-term glucocorticoid therapy (defined as a daily dosage equivalent to 2.5 mg of prednisone or greater for at least 3 months).622 Because of concerns about potential harms (e.g., adverse cardiovascular effects), ACR states that additional study is needed to determine the potential benefits versus risks of calcium and vitamin D supplementation in patients receiving glucocorticoids.622 For additional information on the prevention and treatment of glucocorticoid-induced osteoporosis, see Cautions: Musculoskeletal Effects, in the Corticosteroids General Statement 68:04.

Administration

The acetate, carbonate, citrate, gluconate, lactate, and phosphate salts of calcium are administered orally. It has been recommended that most oral calcium supplements be administered 1-1.5 hours after meals or with a demulcent (e.g., milk). However, calcium carbonate powder (i.e., CAL CARB-HD^®) should generally be administered with meals, since the manufacturer recommends mixing the powder with food for administration. Calcium salts used to bind dietary phosphate in patients with end-stage renal disease should be administered with meals (e.g., 10-15 minutes before, or during, the meal).130

Calcium chloride and calcium gluconate may be administered IV.403 Calcium chloride also may be administered by intraosseous (IO) injection† in the setting of pediatric resuscitation;403 onset of action and systemic concentrations are comparable to those achieved with venous administration.403 Parenteral calcium salts may be administered in large volume IV infusion fluids.

IV calcium injections must be administered slowly at a rate not exceeding 0.7-1.8 mEq/minute, and the injection should be stopped if the patient complains of discomfort. Following IV injection, the patient should remain recumbent for a short time. Close monitoring of serum calcium concentrations is essential during IV administration of calcium. Calcium chloride should not be injected IM or into subcutaneous or perivascular tissue, since severe necrosis and sloughing may occur. Although other calcium salts may cause mild to severe local reactions, they are generally less irritating than calcium chloride. (See Cautions.) The fixed combination of calcium glycerophosphate and calcium lactate is injected IM.142 Although some manufacturers previously stated that calcium gluconate could be injected IM when IV administration was not possible, manufacturers of calcium gluconate currently state that the drug should not be injected IM or into subcutaneous tissue because of the potential for severe local reactions.140,141 In children, calcium salts should not be administered through scalp veins. Oral administration of calcium supplements or calcium-rich foods should replace parenteral calcium therapy as soon as possible.

The interaction of calcium and phosphate in parenteral nutrition solutions is a complex phenomenon; various factors have been identified as playing a role in the solubility or precipitation of a given combination.135 Calcium salts are conditionally compatible with phosphate in parenteral nutrition solutions; incompatibility is dependent on a solubility and concentration phenomenon and is not entirely predictable.135 Precipitation may occur during compounding or at some time after compounding is completed.135 Specialized references should be consulted for specific compatibility information.

Dosage

Dosage of the oral calcium supplements is usually expressed in grams or mg of elemental calcium and depends on the requirements of the individual patient. Dosage of parenteral calcium replacements is usually expressed as mEq of calcium and depends on individual patient requirements. One mEq of elemental calcium is equivalent to 20 mg. See Table 1 for the approximate calcium content of the various calcium salts.

Oral calcium supplements usually are administered in 3 or 4 divided doses daily. Optimum calcium absorption may require supplemental vitamin D in individuals with inadequate vitamin D intake, those with impaired renal activation of the vitamin, or those not receiving adequate exposure to sunlight.112,116

Dietary and Replacement Requirements

Because of insufficient data to establish estimated average requirements (EARs) in infants younger than 1 year of age, the National Academy of Sciences (NAS) has developed adequate intakes (AIs) for calcium in this population (see Uses: Dietary Requirements).153 Calcium requirements in infants are presumed to be met by human milk; thus, AIs developed for this age group are principally based on mean intake data from infants receiving human milk.153 The AI recommended for healthy infants up to 6 months of age is 200 mg daily and for infants 6-12 months of age is 260 mg daily (taking into account additional intake of calcium from food).153

In children and adolescents 1-18 years of age, the recommended dietary reference intake values for calcium are determined based on levels required to support bone accretion and calcium retention.153 Using this approach, the EAR of elemental calcium currently recommended by the NAS for healthy children 1-3, 4-8, or 9-18 years of age is 500, 800, or 1100 mg daily, respectively, and the Recommended Dietary Allowance (RDA) for these respective age groups is 700, 1000, and 1300 mg daily.153 Many chronic illnesses that affect children are associated with abnormalities in calcium metabolism and bone mineralization, and special consideration should be given for different calcium requirements in such children; some such diseases include juvenile rheumatologic conditions, renal disease, liver failure, and certain endocrine disorders, including type 1 (insulin-dependent) diabetes mellitus.112

The goal of calcium intake in adults 19-50 years of age is to promote bone maintenance and neutral calcium balance.153 Based on a series of controlled calcium balance studies in this age group, NAS recommends an EAR of 800 mg daily and an RDA of 1 g daily.153

Calcium intake in adults 51-70 years of age is principally focused on lessening the degree of bone loss that manifests during later stages of adulthood.153 Because of menopause, the natural process of bone loss occurs earlier for women than for men.153 Findings from the Women's Health Initiative (WHI) study revealed modest improvements in BMD and risk of fractures in women 50-79 years of age who received daily supplementation with 1 g calcium plus 400 units vitamin D; however, these results should be interpreted cautiously because of possible confounding factors (e.g., concomitant use of hormone replacement therapy).153 While considering these limitations, NAS states that the emerging evidence indicates that a somewhat higher intake of calcium may be justified in postmenopausal women 51-70 years of age compared with similarly aged men.153 In men 51-70 years of age, the recommended EAR for calcium is 800 mg daily and the RDA is 1 g daily; in women 51-70 years of age, the recommended EAR for calcium is 1 g daily and the recommended RDA is 1.2 g daily.153

Bone loss and resulting risk of fractures are the predominant concerns when developing calcium intake recommendations in adults older than 70 years of age.153 However, a dose-response relationship for calcium and fracture risk has not been established and calcium balance studies are lacking in this age group.153 Given these limitations, NAS recommends the same calcium requirements in adults older than 70 years of age as for those recommended in postmenopausal women (EAR of 1 g daily and RDA of 1.2 g daily).153

Because of adaptive maternal responses to fetal calcium needs (e.g., changes in calciotropic hormones and resultant enhanced calcium absorption) and the fact that the maternal skeleton does not appear to act as a reservoir for fetal calcium needs, calcium requirements are not increased during pregnancy.112 Randomized controlled studies have not demonstrated any additional benefits to the mother or fetus from increased intake of calcium during pregnancy.153 Therefore, the usual calcium recommendations that are appropriate for age in nonpregnant women should be used in pregnant women.153 Likewise, there is no evidence that calcium requirements are increased during lactation and the same calcium intake recommendations are given for lactating as for nonlactating women.153 Physiologic changes occur naturally in maternal bone during and after lactation to provide the infant with calcium without impairing maternal bone mass, and increased calcium intake does not appear to alter this process.153

Calcium replacement requirements can be estimated by clinical condition and/or serum calcium determinations. Prophylactic administration of calcium supplements may be necessary in some patients in order to maintain serum calcium above 9 mg/dL. The average adult oral dosage of elemental calcium for prevention of hypocalcemia is about 1 g daily, and the usual oral dosage for treatment of calcium depletion is 1-2 g or more daily. In children, the usual supplemental dosage of elemental calcium is 45-65 mg/kg daily. In neonatal hypocalcemia, the daily dosage of elemental calcium is 50-150 mg/kg and should not exceed 1 g.

Calcium gluconate is usually administered IV as a 10% solution and calcium chloride as a 2-10% solution. The manufacturers state that the usual initial IV dose of calcium for prompt elevation of serum calcium is 2.3-14 mEq for adults,136,137,138,139,140,141 0.93-2.3 mEq for children,140,141 and less than 0.93 mEq for infants.140,141 It has been recommended that these doses be repeated every 1-3 days depending on the patient's response.136,137,138,139 Alternatively, one manufacturer recommends a pediatric IV dose of 0.272 mEq of calcium per kg, up to a maximum total daily dosage of 1.36-13.6 mEq, in the treatment of hypocalcemic disorders.138 For the treatment of hypocalcemic tetany, 4.5-16 mEq doses of calcium may be administered IV to adults until therapeutic response occurs. In children with hypocalcemic tetany, 0.5-0.7 mEq/kg may be administered IV 3 or 4 times daily or until tetany is controlled. Neonatal tetany may be treated with divided doses totaling about 2.4 mEq/kg daily.

The usual adult IM dosage of the calcium glycerophosphate and calcium lactate fixed-combination preparation given to increase serum calcium concentrations is 0.8 mEq of calcium 1-4 times weekly or as directed by a clinician.142

Advanced Cardiovascular Life Support

Adult Dosage

If calcium administration is necessary during cardiac arrest, an IV dose of 0.109-0.218 mEq/kg (repeated as necessary) using calcium chloride has been recommended.175 Alternatively, adults have been given IV calcium doses of 7-14 mEq using calcium chloride. However, routine administration of calcium in patients with cardiac arrest is not recommended.400,401 (See Advanced Cardiovascular Life Support under Uses: Parenteral Preparations.)

Pediatric Dosage

If administration of calcium is indicated for the treatment of hypocalcemia, calcium-channel blocker overdosage, hypermagnesemia, or hyperkalemia during pediatric resuscitation, experts recommend a pediatric IV or IO† calcium dose of 0.272 mEq/kg using calcium chloride.403 In critically ill children, calcium chloride may provide a greater increase in ionized calcium than calcium gluconate.403 The appropriate dose should be administered by slow IV or IO† injection.403

Other Dosages

When calcium acetate is used orally to control hyperphosphatemia in adults with chronic renal failure, the recommended initial dosage is 1.334 g of calcium acetate (338 mg of calcium) with each meal.113 Dosage may be increased gradually according to serum phosphate concentrations, provided hypercalcemia does not occur.113 The manufacturer states that most patients require about 2-2.67 g (about 500-680 mg of calcium) with each meal.113 However, some experts state that the dosage of calcium provided by calcium-containing phosphate binders should not exceed 1.5 g daily and that the total calcium intake (including dietary calcium) should not exceed 2 g daily.130 These experts state that dialysis patients who remain hyperphosphatemic despite such therapy should receive a calcium-containing phosphate binder in combination with a non-calcium-, non-aluminum-, non-magnesium-containing phosphate binder.130 The manufacturer recommends that serum calcium concentrations be monitored twice weekly during initiation of calcium acetate therapy and subsequent dosage adjustment; serum phosphorus concentrations also should be monitored periodically.113 If hypercalcemia occurs, dosage should be reduced or the salt should be withheld.113 If severe hypercalcemia occurs, specific measures (e.g., hemodialysis) for the management of overdosage may be necessary.113 Patients should be advised of the importance of dosage compliance, adherence to instructions about diet, and avoidance of concomitant use of antacids or other preparations containing clinically important concentrations of calcium.113,127 Patients also should be advised of potential manifestations of hypercalcemia.113

For the treatment of hyperkalemia with secondary cardiac toxicity, 2.25-14 mEq of calcium may be administered IV while monitoring the ECG. Doses may be repeated after 1-2 minutes if necessary.

Magnesium intoxication in adults is treated initially with 7 mEq of IV calcium; subsequent doses should be adjusted according to patient response. Alternatively, for the treatment of hypermagnesemia in adults, an IV calcium dose of 6.8-13.6 mEq using 10% calcium chloride (5-10 mL) has been administered, and repeated as necessary.196

For the treatment of drug-induced cardiovascular emergencies associated with calcium-channel blocking agent toxicity in pediatric patients, an IV calcium dose of 0.272 mEq/kg using 10% calcium chloride (0.2 mL/kg) has been administered over 5-10 minutes; if a beneficial effect was observed, an IV calcium infusion of 0.27-0.68 mEq/kg per hour using calcium chloride has been administered.403 Ionized calcium concentrations should be monitored to prevent hypercalcemia.403

Calcium is also administered IV during exchange transfusions in neonates in a dosage of 0.45 mEq of calcium after every 100 mL of citrated blood exchanged. In adults receiving transfusions of citrated blood, about 1.35 mEq of calcium should be administered IV concurrently with each 100 mL of citrated blood.

In the calcium infusion test†, calcium is given IV in a dosage of 0.25 mEq/kg per hour for a 3-hour period; serum gastrin concentrations are determined 30 minutes before the infusion, at the start of the infusion, and at 30-minute intervals thereafter for 4 hours. In most patients with Zollinger-Ellison syndrome, preinfusion serum gastrin concentrations increase by more than 50% or by greater than 500 pg/mL during the infusion. In the diagnosis of medullary thyroid carcinoma†, about 7 mEq of calcium is given IV over 5-10 minutes. In patients with medullary thyroid carcinoma, plasma calcitonin concentrations are elevated above normal basal concentrations.

Local Effects

Calcium salts are irritating to tissue when administered by IM or subcutaneous injection and cause mild to severe local reactions including burning, necrosis and sloughing of tissue, cellulitis, and soft tissue calcification; venous irritation may occur with IV administration. When injected IV, calcium salts should be administered slowly through a small needle into a large vein to avoid too rapid an increase in serum calcium and extravasation of calcium solution into the surrounding tissue with resultant necrosis. Patients may complain of tingling sensations, a sense of oppression or heat waves, and a calcium or chalky taste following IV administration of calcium salts.

Cardiovascular Effects

Rapid IV injection of calcium salts may cause vasodilation, decreased blood pressure, bradycardia, cardiac arrhythmias, syncope, and cardiac arrest.

GI Effects

Orally administered calcium salts may be irritating to the GI tract. Calcium salts also may cause constipation. Calcium chloride, by any route of administration, produces more irritation than the other calcium salts and has been reported to cause GI hemorrhage when taken orally.

Hypercalcemia

Hypercalcemia is rarely produced by administration of calcium alone, but may occur when large doses are given to patients with chronic renal failure. Since hypercalcemia may be more dangerous than hypocalcemia, overtreatment of hypocalcemia should be avoided. Mild hypercalcemia may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting, with mental changes such as confusion, delirium, stupor, and coma becoming evident as the degree of hypercalcemia increases.113 Mild hypercalcemia usually is readily controlled by reducing calcium intake (e.g., decreasing the dose of or avoiding supplemental calcium); more severe hypercalcemia may require specific management (e.g., hemodialysis).113 In dialysis patients with chronic renal failure receiving calcium salts, adjustments in calcium concentrations in the dialysate may be necessary to reduce the risk of hypercalcemia.113,126 The long-term effect of chronic calcium administration (e.g., in patients with chronic renal failure receiving calcium salts to control hyperphosphatemia) on progression of vascular or soft-tissue calcification is not known.113,127

Renal Calculi

Because the principal constituents of most renal calculi (kidney stones) are calcium salts, a high dietary intake of calcium has long been suspected as contributing to the risk of renal calculi, and restriction of calcium intake (i.e., low-calcium diets) had long been considered a reasonable measure in an attempt to prevent calculi formation in patients with idiopathic hypocalciuria.122,123,124 However, recent evidence from studies in men 40-75 years of age with no history of kidney stones and in women 34-59 years of age participating in the Nurses'; Health Study I indicates that high dietary intake of calcium actually decreases the risk of symptomatic renal calculi, while intake of supplemental calcium may increase the risk of symptomatic stones.122,123,124 High calcium intake can reduce urinary oxalate excretion, which is thought to lower the risk of renal calculi.122,123,124 In addition, dietary calcium can reduce the GI absorption of oxalate.122 Therefore, differences in calculi risk between high dietary calcium intake and calcium supplementation may be associated in part with differences in the timing of calcium ingestion relative to oxalate consumption or with other factors present in dairy products (the principal source of dietary calcium) that are not present in supplements.122

Precautions and Contraindications

Frequent determinations of serum calcium concentrations should be performed, and serum calcium concentrations should be maintained at 9-10.4 mg/dL (4.5-5.2 mEq/L). Some clinicians prefer to maintain serum calcium at slightly lower concentrations. Serum calcium concentrations usually should not be allowed to exceed 12 mg/dL. Administration of calcium in patients who have received transfusions of citrated blood may result in higher than normal total serum calcium concentrations. In these patients, however, most of the excess calcium is bound to citrate and is inactive; therefore, serious toxicity usually does not result. Although determinations of urine calcium have been advised, they are generally unreliable and hypercalciuria can occur in the presence of hypocalcemia. Some clinicians recommend forcing fluids to produce increased urine volume and thus prevent the formation of renal stones in patients with hypercalciuria. When hypercalcemia occurs, discontinuance of the drug is usually sufficient to return serum calcium concentrations to normal.

Calcium salts should be used cautiously, if at all, in patients with sarcoidosis, renal or cardiac disease, and in patients receiving cardiac glycosides. (See Drug Interactions: Cardiac Glycosides.) Calcium salts are contraindicated in patients with ventricular fibrillation or hypercalcemia. IV administration of calcium is contraindicated when serum calcium concentrations are above normal.

Bisphosphonates

Concomitant administration of calcium salts with bisphosphonates (e.g., alendronate, etidronate, ibandronate, risedronate) may reduce absorption of the bisphosphonate from the GI tract.150 To minimize this effect, the drugs should be administered at separate times.150

Cardiac Glycosides

The inotropic and toxic effects of cardiac glycosides and calcium are synergistic and arrhythmias may occur if these drugs are given together (particularly when calcium is given IV). IV administration of calcium should be avoided in patients receiving cardiac glycosides, particularly if digoxin toxicity is suspected; if necessary, calcium should be given slowly in small amounts.

Iron Preparations

Concomitant administration of calcium salts and oral iron preparations may result in reduced absorption of iron.149,150 Patients should be advised to take the drugs at different times, whenever possible.149,150

Levothyroxine

Calcium carbonate may form an insoluble chelate with levothyroxine, resulting in decreased levothyroxine absorption and increased serum thyrotropin concentrations.143,150 To minimize or prevent this interaction, oral levothyroxine sodium should be administered at least 4 hours apart from calcium carbonate.143

Quinolones

Concomitant administration of calcium salts and some fluoroquinolones (e.g., ciprofloxacin) may reduce oral bioavailability of the fluoroquinolone.151,152 For further information, including any specific instructions regarding timing of drug administration when concomitant use is necessary, see the individual monographs for quinolones in 8:12.18.

Tetracyclines

Calcium complexes tetracycline antibiotics rendering them inactive; the 2 drugs should not be given at the same time orally nor should they be mixed for parenteral administration.

For further information on drug interactions with calcium salts, see Drug Interactions in Antacids 56:04.

Laboratory Test Interferences

Transient elevations of plasma 11-hydroxycorticosteroid concentrations (Glenn-Nelson technique) may occur when IV calcium is administered, but concentrations return to control values after 1 hour. In addition, IV calcium salts can produce false-negative values for serum and urinary magnesium as measured by the Titan yellow method.

Pharmacology

Calcium is essential for maintenance of the functional integrity of nervous, muscular, and skeletal systems and cell-membrane and capillary permeability. The cation is an important activator in many enzymatic reactions and is essential to a number of physiologic processes including transmission of nerve impulses; contraction of cardiac, smooth, and skeletal muscles; renal function; respiration; and blood coagulation. Calcium also plays regulatory roles in the release and storage of neurotransmitters and hormones, in the uptake and binding of amino acids, and in cyanocobalamin (vitamin B₁₂) absorption and gastrin secretion. There is evidence indicating an inverse relationship between calcium intake and blood pressure101,102,103,120,121 and that calcium supplementation may be associated with a reduction in blood pressure in healthy young adults104,120,121 and healthy pregnant women105 and in some patients with hypertension;103,106,120,121 however, further study is needed to evaluate further the role of calcium in blood pressure regulation.101,102,103,104,105,106,107,108

Calcium accounts for 1-2% of adult body weight, and more than 99% of total body calcium is found in bone and teeth.112 Calcium also is present in blood, extracellular fluid, muscle, and other tissues where it has roles in mediating vascular contraction and vasodilation, muscle contraction, nerve transmission, and glandular secretion.112 Calcium is present in bone mainly as hydroxyapatite, with bone mineral content representing about 40% of bone weight.112 Bone is a dynamic tissue that constantly undergoes osteoclastic bone resorption and osteoblastic bone formation, with a portion of bone being remodeled (reabsorbed and replaced with new bone) each year.112 Formation exceeds resorption in growing children, is balanced with resorption in healthy adults, and lags behind resorption after menopause and with aging in both genders.112 The rate of cortical (compact) bone remodeling can be as high as 50% annually in young children and is about 5% annually in adults; trabecular (cancellous) bone remodeling is about fivefold that of cortical remodeling in adults.112 In addition to serving as a structural support for the body, the skeleton also serves as a reservoir for calcium.112 Although both exercise and calcium intake influence bone mass, it currently is unclear whether calcium intake influences the degree of benefit on bone derived from exercise.112

Conditions associated with reduced concentrations of circulating estrogen alter calcium homeostasis.112 Exercise-induced amenorrhea results in reduced calcium retention and lower bone mass, and anorexia-induced amenorrhea results in reduced net calcium absorption, increased urinary calcium excretion, and a reduced rate of bone formation, when compared with eumenorrheic women.112 Decreased estrogen production at menopause is associated with accelerated bone loss, particularly from the lumbar spine, for about 5 years, during which time skeletal mass loss averages about 3% per year.112 Reduced estrogen concentrations are associated with reduced calcium absorption efficiency and increased bone turnover rates.112 While it is unclear whether the principal effect of estrogens on calcium is at the skeletal or intestinal level, examination of the skeletal response to calcium supplementation in premenopausal and early postmenopausal women indicates that increased calcium intake will not prevent the rapid trabecular bone loss that occurs during the first 5 years after menopause and that the calcium intake requirement for women does not appear to change acutely with menopause.112,126 Calcium responsiveness of cortical bone appears to depend less on menopausal status than does that of trabecular bone.112 Calcium requirements in vegetarians may be increased because of the negative effects of oxalate and phytate (present in high concentrations in vegetarian diets) on calcium bioavailability.112 Because lactose-intolerant individuals often avoid consumption of dairy products, the principal source of calcium in the US and Canada, they may be calcium deficient; however, there is no evidence to indicate that lactose intolerance influences the calcium requirement per se, although it may negatively influence calcium intake.112

Pharmacokinetics

Absorption

Calcium is absorbed from the GI tract by active transport and passive diffusion. Calcium is actively absorbed in the duodenum and proximal jejunum and, to a lesser extent, in the more distal segments of the small intestine. The degree of absorption depends on a number of factors; calcium is never completely absorbed from the intestine. For absorption to occur, calcium must be in a soluble, ionized form. The efficiency of intestinal calcium absorption may be increased when calcium intake is reduced and during pregnancy and lactation when calcium requirements are higher than normal. However, when hypocalcemia is caused by deficiency of either parathyroid hormone or vitamin D, calcium absorption decreases. As serum calcium concentration rises, negative feedback control by parathyroid hormone results in decreased calcium absorption. Vitamin D, in its activated forms, is required for calcium absorption and increases the capability of the absorptive mechanisms. Active transport of calcium into enterocytes and out on the serosal side of the intestinal mucosa depends on the action of activated vitamin D (1,25-dihydroxyvitamin D) and its intestinal receptors; this mechanism accounts for most of the calcium absorption from the GI tract at low and moderate intake levels.112 Calcium also diffuses passively between intestinal mucosal cells, depending on the luminal:serosal concentration gradient of the ion; the importance of passive diffusion increases with high calcium intakes.112 An acidic intestinal pH is necessary for ionization of calcium; thus an alkaline pH impedes absorption.

Oral bioavailability of calcium from nonfood sources and supplements depends on intestinal pH, the presence or absence of a meal, and the dose.112 When a 250-mg dose of calcium is administered with a standardized breakfast, average oral bioavailability in adults ranges from 25-35% with various salts; under the same conditions, absorption from milk was about 29%.112 Calcium absorption is decreased in the absence of a meal.112 The extent of calcium absorption from supplements is greatest when calcium is taken in doses of 500 mg or less.112

Fractional calcium absorption varies with age, being highest during infancy (about 60%), declining to about 28% in prepubertal children, and rising again during early puberty (about 34%); fractional absorption remains at about 25% in young adults, although it increases during the last 2 trimesters of pregnancy.112 With aging, fractional absorption declines, decreasing on average by 0.21% annually in postmenopausal women.112 Similar declines also appear to occur with aging in men.112

Absorption is retarded by certain anions (e.g., oxalates, phytates, sulfates) and by fatty acids which precipitate or complex calcium ions; however, an intestinal pH of 5-7 facilitates maximal dissolution and dissociation of these complexes. As a result, calcium may be poorly absorbed from foods rich in oxalic acid (e.g., spinach, sweet potatoes, rhubarb, beans) or phytic acid (e.g., unleavened bread, raw beans, seeds, nuts, grains, soy isolates).112 Although soybeans contain high concentrations of phytic acid, calcium absorption is relatively high from this food.112 Glucocorticoids and low serum concentrations of calcitonin may depress the absorption of calcium. Calcium absorption is decreased in patients with certain disease states such as achlorhydria, renal osteodystrophy, steatorrhea, or uremia.

IM or IV administered calcium salts are absorbed directly into the blood stream. Following IV injection of calcium salts, serum calcium concentrations increase almost immediately and may return to previous values in 30 minutes to 2 hours.

Distribution

Following absorption, calcium first enters the extracellular fluid and is then rapidly incorporated into skeletal tissue. Bone formation, however, is not stimulated by administration of calcium. Bone contains 99% of the body's calcium; the remaining 1% is distributed equally between the intracellular and extracellular fluids.

Normal total serum calcium concentrations range from 9-10.4 mg/dL (4.5-5.2 mEq/L), but only ionized calcium is physiologically active. Serum calcium concentrations are not necessarily accurate indications of total body calcium; total body calcium may be decreased in the presence of hypercalcemia, and hypocalcemia can occur even though total body calcium is increased. Of the total serum calcium concentration, 50% is in the ionic form and 5% is complexed by phosphates, citrates, and other anions. Approximately 45% of the serum calcium is bound to plasma proteins; for a change in serum albumin of 1 g/dL, the serum calcium concentration may change about 0.8 mg/dL (0.04 mEq/dL). Hyperproteinemia is associated with increased total serum calcium concentrations; in hypoproteinemia, total serum calcium concentrations decrease. Acidosis results in increased concentrations of ionic calcium, while alkalosis promotes a decrease in the ionic serum calcium concentration.

CSF concentrations of calcium are about 50% of serum calcium concentrations and tend to reflect ionized serum calcium concentrations. Calcium crosses the placenta and reaches higher concentrations in fetal blood than in maternal blood. Calcium is distributed into milk.

Elimination

Calcium is excreted mainly in the feces and consists of unabsorbed calcium and that secreted via bile and pancreatic juice into the lumen of the GI tract. Most of the calcium filtered by renal glomeruli is reabsorbed in the ascending limb of the loop of Henle and proximal and distal convoluted tubules. Only small amounts of the cation are excreted in urine. Parathyroid hormone, vitamin D, and thiazide diuretics decrease urinary excretion of calcium, whereas other diuretics, calcitonin, and growth hormone promote renal excretion of the cation. Urinary excretion of calcium decreases with reduction of ionic serum calcium concentrations but is proportionately increased as serum ionized calcium concentrations increase. In healthy adults on a regular diet, urinary excretion of calcium may be as high as 250-300 mg daily. With low calcium diets, urinary excretion usually does not exceed 150 mg daily. Urinary excretion of calcium decreases during pregnancy and in the early stages of renal failure. Urinary excretion of calcium decreases with aging, possibly because of age-related decreases in intestinal calcium absorption efficiency and an associated decrease in filtered calcium load.112 Endogenous fecal calcium excretion does not change appreciably with aging.112 Calcium is also excreted by the sweat glands.

Chemistry and Stability

Chemistry

Calcium is an essential nutrient cation, and calcium salts are used for the prevention or treatment of calcium depletion. For oral administration, the acetate, carbonate, citrate, gluconate, lactate, and phosphate salts of calcium are available as single ingredients and/or as components of combination products. The chloride, gluconate, and a combination of the glycerophosphate and lactate salts are available as injections.

Calcium chloride is freely soluble, and calcium lactate and calcium acetate are soluble in water. Calcium gluconate and calcium glycerophosphate are sparingly soluble, and the carbonate and phosphate salts of calcium are insoluble in water. Calcium chloride is deliquescent, and calcium lactate is somewhat efflorescent. Calcium gluconate injection may contain small amounts of calcium d-saccharate or other calcium salts as stabilizers and has a pH of 6-8.2. Calcium chloride injection has a pH of 5.5-7.5 and calcium glycerophosphate-calcium lactate injection has a pH of about 7.

Stability

The interaction of calcium and phosphate in parenteral nutrition solutions is a well-documented, but complex, phenomenon (see Dosage and Administration: Administration).135 Calcium injections have been reported to be incompatible with IV solutions containing various drugs. Published data are too varied and/or limited to permit generalizations, and specialized references should be consulted for specific compatibility information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

100. National Institutes of Health Office of Medical Applications of Research. Consensus conference: osteoporosis. JAMA . 1984; 252:799-802. [PubMed 6748181]

101. McCarron DA, Morris CD, Cole C. Dietary calcium in human hypertension. Science . 1982; 217:267-9. [PubMed 7089566]

102. McCarron DA, Morris CD, Henry HJ et al. Blood pressure and nutrient intake in the United States. Science . 1984; 224:1392-8. [PubMed 6729459]

103. Kaplan NM. Non-drug treatment of hypertension. Ann Intern Med . 1985; 102:359-73. [PubMed 3882040]

104. Belizan JM, Villar J, Pineda O et al. Reduction of blood pressure with calcium supplementation in young adults. JAMA . 1983; 249:1161-5. [PubMed 6337285]

105. Belizan JM, Villar J, Zalazar A et al. Preliminary evidence of the effect of calcium supplementation on blood pressure in normal pregnant women. Am J Obstet Gynecol . 1983; 146:175-80. [PubMed 6846435]

106. McCarron DA, Morris CD. Blood pressure response to oral calcium in persons with mild to moderate hypertension: randomized, double-blind, placebo-controlled, crossover trial. Ann Intern Med . 1985; 103(6 Part 1): 825-31. [PubMed 3904559]

107. Resnick LM. Calcium and hypertension: the emerging connection. Ann Intern Med . 1985; 103(6 Part 1): 944-6. [PubMed 4062094]

108. Heath H III, Callaway CW. Calcium tablets for hypertension? Ann Intern Med . 1985; 103(6 Part 1): 946-7. Editorial.

110. National Research Council Subcommittee on the Tenth Edition of the RDAs. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press; 1989:174-84.

111. Prince RL, Smith M, Dick IM et al. Prevention of postmenopausal osteoporosis: a comparative study of exercise, calcium supplementation, and hormone-replacement therapy. N Engl J Med . 1991; 325:1189-95. [PubMed 1922205]

112. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press; 1997. (Uncorrected proofs.)

113. Braintree Laboratories. PhosLo^® (calcium acetate) tablets prescribing information (dated May 1992). In: Physicians'; desk reference. 52nd ed. Montvale, NJ; 1998:733-4.

115. Allender PS, Cutler JA, Follmann D et al. Dietary calcium and blood pressure: a meta-analysis of randomized clinical trials. Ann Intern Med . 1996; 124:825-31. [PubMed 8610952]

116. National Institutes of Health. Optimum calcium intake. NIH consensus statement 1994 Jun 6-8; 12(4):1-31.

117. Levine RJ, Hauth JC, Curet LB et al. Trial of calcium to prevent preeclampsia. N Engl J Med . 1997; 337:69-76. [PubMed 9211675]

118. Roberts JM. Prevention and early treatment of preeclampsia. N Engl J Med . 1997; 337:124-5. [PubMed 9211683]

120. Bucher HC, Cook RJ, Guyatt GH et al. Effects of dietary calcium supplementation on blood pressure: a meta-analysis of randomized controlled trials. JAMA . 1996; 275:1016-1022. [PubMed 8596234]

121. McCarron DA, Hatton D. Dietary calcium and lower blood pressure: we all can benefit. JAMA . 1996; 275:1128-9. [PubMed 8601935]

122. Curhan GC, Willett WC, Speizer FE et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med . 1997; 126:497-504. [PubMed 9092314]

123. Curhan GC, Willett WC, Rimm EB et al. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med . 1993; 328:833-8. [PubMed 8441427]

124. Coe FL, Parks JH, Favus MJ. Diet and calcium: the end of an era? Ann Intern Med . 1997; 126:553-5. Editorial.

125. Bucher HC, Guyatt GH, Cook RJ et al. Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia: a meta-analysis of randomized controlled trials. JAMA . 1996; 275:1113-7. [PubMed 8601931]

126. European Foundation for Osteoporosis and Bone Disease, National Osteoporosis Foundation, and National Institute of Arthritis and Musculoskeletal and Skin Disease. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med . 1993; 94:646-50. [PubMed 8506892]

127. National Institutes of Health Consensus Development Conference Panel. Morbidity and mortality of renal dialysis: an NIH consensus conference statement. Ann Intern Med . 1994; 121:62-70. [PubMed 8198352]

129. Anon. Drugs for prevention and treatment of postmenopausal osteoporosis. Med Lett Drugs Ther . 2000; 42:97-100. [PubMed 11035622]

130. National Kidney Foundation. Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Guideline 5. Use of phosphate binders in CKD. 2003. Available at [Web]. Accessed 2005 Mar 22.

131. Genzyme. Renagel^® (sevelamer hydrochloride) capsules and tablets prescribing information. Cambridge, MA; 2000 Jul.

132. Shire US Inc. Fosrenol^® (lanthanum carbonate) chewable tablets prescribing information. Wayne, PA; 2004 Oct.

133. Loghman-Adham M. Safety of new phosphate binders for chronic renal failure. Drug Saf . 2003; 26:1093-15. [PubMed 14640773]

135. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:245-6.

136. Hospira. Calcium chloride Abboject^® injection prescribing information. Lake Forest, IL; 2004 Oct.

137. Hospira. Calcium chloride Ansyr^® injection prescribing information. Lake Forest, IL; 2004 Jun.

138. IMS. Calcium chloride injection prescribing information. South El Monte, CA; 2000 Feb.

139. American Regent. Calcium chloride injection prescribing information. Shirley, NY; 2006 Sep.

140. APP. Calcium gluconate injection prescribing information. Schaumburg, IL; 2007 Dec.

141. American Regent. Calcium gluconate injection prescribing information. Shirley, NY; 2000 Feb.

142. Glenwood, LLC. Calphosan^® (calcium lactate/calcium glycerophosphate) injection prescribing information. Englewood, NJ; 2008 Apr. Available at [Web]. Accessed 2008 Oct 22.

143. Abbott Laboratories. Synthroid^® (levothyroxine sodium) tablets prescribing information. North Chicago, IL; 2008 Mar.

147. Cosman F, de Beur SJ, LeBoff MS et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int . 2014; 25:2359-81. [PubMed 25182228]

148. Watts NB, Bilezikian JP, Camacho PM et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract . 2010 Nov-Dec; 16 Suppl 3:1-37. [PubMed 21224201]

149. Iron salts/antacids. In: Tatro DS, ed. Drug Interactions Facts. St. Louis, MO: Wolters Kluwer Health; 2008:419.

150. Rizzoli R, Reginster JY, Boonen S et al. Adverse reactions and drug-drug interactions in the management of women with postmenopausal osteoporosis. Calcif Tissue Int . 2011; 89:91-104. [PubMed 21637997]

151. Quinolones/antacids. In: Tatro DS, ed. Drug Interactions Facts. St. Louis, MO: Wolters Kluwer Health; 2008:610.

152. Bayer. Cipro^® (ciprofloxacin hydrochloride tablets and ciprofloxacin oral suspension) prescribing information. Wayne, NJ; 2008 Oct.

153. Institute of Medicine. Dietary reference intakes for adequacy: calcium and vitamin D. In: Ross CA, Taylor CL, Yaktine AL, and Del Valle HB, eds. Dietary reference intakes for calcium and vitamin D. Washington DC: The National Academies Press; 2011:345-402. [Web]

175. The American Heart Association. Guidelines 2005 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005; 112(Suppl I): IV1-211.

196. Vanden Hoek TL, Morrison LJ, Shuster M et al. Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S829-61.

400. Link MS, Berkow LC, Kudenchuk PJ et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2015; 132(18 Suppl 2):S444-64. [PubMedCentral]

401. Neumar RW, Otto CW, Link MS et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S729-67.

402. de Caen AR, Berg MD, Chameides L et al. Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2015; 132(18 Suppl 2):S526-42. [PubMed 26473000]

403. Kleinman ME, Chameides L, Schexnayder SM et al. Part 14: pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S876-908. [PubMedCentral]

622. Buckley L, Guyatt G, Fink HA et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol . 2017; 69:1521-1537. [PubMed 28585373]