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182

The portion of plasma calcium that is not bound to protein is filtered by the

glomerulus. Approximately 97% to 99.5% of the filtered calcium is reabsorbed: 60%

in the proximal tubule, 20% in the ascending limb, 10% in the distal tubule, and 3%

to 10% in the collecting duct. Approximately 20% of the calcium in the kidney tubule

is ionized, whereas the remainder is bound to anions such as citrate, sulfate,

phosphate, and gluconate. The extent of calcium reabsorption depends on the

presence of specific anions and also on the urine pH, which affects the fraction of

calcium bound to anions. Passive reabsorption at the proximal convoluted tubule is

linked closely to sodium transport and is increased by ECF contraction and

decreased by volume expansion. At the proximal straight tubule, the transport process

is active and dissociable from sodium and water transport. PTH increases the

calcium reabsorption at the distal tubule and also at the collecting duct independent

of sodium reabsorption. Acidosis can also increase renal calcium excretion by

inhibiting tubular reabsorption and by increasing the ultrafiltrable calcium through

reduced binding of calcium to plasma proteins. Conversely, alkalosis promotes

calcium protein binding, thus reducing the amount of ultrafiltrable calcium. It also

induces hypocalciuria independent of PTH. Phosphorus administration reduces renal

calcium excretion, whereas phosphorus depletion increases urinary calcium

elimination. Normally, approximately 50 to 300 mg of calcium is excreted by the

kidneys daily, but this can be increased to 600 mg/day.

183

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p. 588

The other important factor regulating plasma calcium concentration is bone

metabolism. The rate of bone turnover and calcium resorption is influenced by PTH,

1,25-dihydroxyvitamin D3

, and calcitonin.

Hypercalcemia

ETIOLOGY

CASE 27-11

QUESTION 1: A.C., a 62-year-old woman, is brought to the hospital by family members because she has

become increasingly lethargic and unresponsive during the past several days. Approximately 4 years ago she

underwent a radical mastectomy and node dissection followed by radiation and chemotherapy for breast

carcinoma. Despite several courses of chemotherapy, she developed metastasis to the bone. About 1 week

before this admission, A.C. complained of fatigue, muscle weakness, and anorexia. Since then, she has spent

most of her time in bed and has had very limited oral intake. Medications taken before admission included

hydrochlorothiazide, oral morphine sulfate, and tamoxifen. Physical examination reveals a dehydrated, cachectic

woman responsive only to painful stimuli. Vital signs include BP, 100/60 mm Hg, and RR, 16 breaths/minute.

Pertinent laboratory values are as follows:

Na, 138 mEq/L

K, 4.5 mEq/L

Cl, 99 mEq/L

CO2

, 33 mEq/L

BUN, 40 mg/dL

Creatinine, 1.2 mg/dL

Calcium, 19 mg/dL

Phosphate, 4.5 mg/dL

Albumin, 3.0 g/dL

The ECG revealed a shortened QT interval. What are the common causes of hypercalcemia? Which of

these might be responsible for the hypercalcemia seen in A.C.?

Malignancy

Malignancy and primary hyperparathyroidism are the most common causes of

hypercalcemia. Hematologic malignancies, such as multiple myeloma, tend to be

responsible for more hypercalcemia than are solid tumors. Cancer of the breast, lung,

head and neck, and renal cell carcinoma are solid tumors commonly associated with

hypercalcemia. Malignancy can cause paraneoplastic hypercalcemia secondary to

bone metastasis, which results in increased bone resorption. Alternatively, patients

may exhibit hypercalcemia in the absence of bone metastasis owing to the production

of osteolytic humoral factors by the tumor. The mediators secreted may be PTH,

PTH-like substances, prostaglandins, cytokines, transforming growth factor-α, and

tumor necrosis factor.

184

Hyperparathyroidism

Hyperparathyroidism is the other common cause of hypercalcemia. Although the

etiology of primary hyperparathyroidism is unclear, women tend to experience the

condition more frequently, especially in the fourth to sixth decades of life.

Approximately 75% of patients have a single adenoma, whereas much smaller

percentages of patients have multiglandular disease, hyperplasia, or carcinoma.

184

Other conditions that can result in hypercalcemia include postkidney transplantation,

immobilization, vitamin A intoxication, hyperthyroidism, Addison disease, and

pheochromocytoma. Hypercalcemia can also occur secondary to increased intestinal

calcium absorption because of vitamin D intoxication, sarcoidosis, and other

granulomatous diseases. Use of thiazide diuretics, lithium, estrogens, and tamoxifen,

as well as excessive calcium ingestion together with alkali (milk-alkali syndrome),

may result in hypercalcemia.

A.C.’s breast cancer bone metastasis, volume contraction, and use of

hydrochlorothiazide and tamoxifen may all contribute to her hypercalcemia.

CLINICAL MANIFESTATIONS

CASE 27-11, QUESTION 2: How is hypercalcemia manifested in A.C.?

The clinical presentations of hypercalcemia vary substantially among patients, but

the severity of the symptoms correlates well with free calcium concentrations.

185 The

specific presentation depends on the rate of serum calcium concentration elevation,

the presence of malignancy, the PTH concentration, and the patient’s age. Concurrent

electrolyte and metabolic abnormalities and underlying diseases will also have an

effect. Because calcium is an important regulator of many cellular functions,

hypercalcemia can produce abnormalities in the neurologic, cardiovascular,

pulmonary, renal, GI, and musculoskeletal systems. As seen in A.C., the signs and

symptoms can be nonspecific: fatigue, muscle weakness, anorexia, thirst, polyuria,

dehydration, and a shortened QT interval on the ECG.

The effect of hypercalcemia on the central nervous system includes lethargy,

somnolence, confusion, headache, seizures, cerebellar ataxia, altered personality,

acute psychosis, depression, and memory impairment. The neuromuscular

manifestations include weakness, myalgia, hyporeflexia or areflexia, and arthralgia.

Symptoms of impaired renal function include polyuria, nocturia, and polydipsia.

These may reflect a defective concentrating ability, possibly because of resistance to

the effects of ADH.

186 The GFR may be decreased because of afferent arteriolar

vasoconstriction, and if hypercalcemia is prolonged, nephrolithiasis,

nephrocalcinosis, chronic interstitial nephritis, and renal tubular acidosis may be

present. Hypermagnesuria and metabolic alkalosis may also be observed.

183

Calcium has a positive inotropic effect and reduces heart rate, similar to cardiac

glycosides. ECG changes indicative of slow conduction, with prolonged PR and

QRS intervals and shortened QT intervals, are commonly seen. In severe

hypercalcemia, increased QT intervals, widened T waves, and arrhythmia may be

present.

183,187

The GI symptoms of hypercalcemia are related primarily to the depressive action

of calcium on smooth muscle and nerve conduction. Constipation, anorexia, nausea,

and vomiting result from reduced GI motility and delayed gastric emptying. Duodenal

ulcer can occur because of increased acid and gastrin secretion. Pancreatitis can

occur during acute hypercalcemia owing to the blockade of the pancreatic ducts

caused by intraductal calcium deposits.

183 Proteolytic enzymes may also be activated

by calcium to cause tissue damage. Both ulcer disease and pancreatitis are more

common in hypercalcemia associated with primary hyperparathyroidism; they are

less likely to be seen in patients with malignancy-induced hypercalcemia.

179

Treatment

CASE 27-11, QUESTION 3: After vigorous fluid resuscitation with IV saline, combined saline and

furosemide diuresis was instituted in A.C. Her serum calcium concentration declined very slowly, prompting the

use of calcitonin. Despite initial success, the serum calcium concentration rose to pretreatment values within 24

hours. Higher dosages of calcitonin could have been attempted at this point; however, pamidronate was used

instead. Her serum calcium concentration finally stabilized at 8 mg/dL after several days of therapy. What was

the rationale for each of these regimens? What other agents are available for hypercalcemia treatment?

p. 588

p. 589

Several therapeutic approaches are used to lower serum calcium concentration:

increasing urinary calcium excretion, inhibiting release of calcium from bone,

reducing intestinal calcium absorption, and enhancing calcium complex formation

with chelating agents. The underlying disease that causes the hypercalcemia should

also be treated, if possible. The specific treatment used depends on the serum ionized

calcium concentration, the presenting signs and symptoms, and the severity and

duration of hypercalcemia. Immediate therapy was needed for A.C., who had

symptoms consistent with severe hypercalcemia.

Specific interventions are described in the subsequent paragraphs, but as an

overview, hydration and diuresis with furosemide generally are the first steps in the

acute treatment of hypercalcemia. If these measures fail to reduce the serum calcium

concentration adequately, several other agents can be added. Calcitonin provides a

rapid onset of hypocalcemic effect, but its duration of action is relatively short. Thus,

a bisphosphonate could be used to elicit a longer hypocalcemic response. Gallium

nitrate is an alternative, but it is not commonly used. Other agents, such as inorganic

phosphates, glucocorticoids, and prostaglandin inhibitors, also have been used to

treat hypercalcemia with varying success (Table 27-4).

Hydration and Diuresis

As noted, the first-line emergency treatment for hypercalcemia is hydration and

volume expansion. Most patients with hypercalcemia are volume-depleted because

of the accompanying polyuria, nausea, and vomiting. Normal saline 1 to 2 L is

commonly given to correct the fluid deficit and to expand extracellular volume,

which will increase urinary calcium excretion by increasing the GFR and inhibiting

calcium reabsorption in the proximal tubule. Because both sodium and calcium are

reabsorbed at the same site in the proximal tubule, saline hydration will reduce the

reabsorption of both cations simultaneously. A.C. was hypotensive and appeared

dehydrated; therefore, saline hydration was used initially to treat the hypercalcemia.

In patients who have renal failure or HF, saline hydration and forced diuresis should

be avoided.

After adequate volume repletion has been established, IV furosemide can be

administered to augment calciuresis. Furosemide blocks the reabsorption of sodium,

chloride, and calcium at the thick ascending limb of Henle’s loop. Doses of 80 to 100

mg every 2 to 4 hours can be used until a sufficient decline of the serum calcium

concentration is attained.

188 Smaller doses (20–40 mg) commonly are given to avoid

the significant loss of fluid and electrolytes caused by the more aggressive regimen.

Adequate amounts of sodium, potassium, magnesium, and fluid should be used to

replace any therapy-induced electrolyte abnormalities. Fluid balance as well as

serum and urine concentrations of these electrolytes must be monitored closely. Urine

flow must be maintained and the renal loss of sodium chloride must be replaced to

preserve the calciuric effect of furosemide.

189

In A.C., the decline of serum calcium

concentration was slow, possibly because of inadequate restoration of plasma

volume, replacement of renal sodium loss, or both. More aggressive hydration with

adequate sodium replacement ensures that the efficacy of furosemide is not

compromised.

Table 27-4

Treatment of Hypercalcemia

Intervention Dose Comment

Saline and

furosemide

1–2 L NS; then furosemide 80 to 100 mg

every 2 to 4 hours.

Establish and maintain normovolemia.

Other electrolytes as needed.

Saline diuresis and volume expansion

depresses Ca

2+ reabsorption in tubules.

Lowers (Ca

2+) within 24 hours. Treatment

of choice in patients without HF or renal

failure.

Calcitonin Four international units/kg SC or IM every

12 hours.

↑ Dose or use another therapy if

unresponsive after 24 hours (Max: 8

international units/kg every 6 hours).

Inhibits osteoclast resorption and renal

reabsorption of calcium. Preferred secondline agent because it has a rapid onset (6

hours) and is nontoxic. It can be used safely

in HF and renal failure. Nausea is the major

adverse effect. Tolerance occurs in 24 to

72 hours. Concomitant plicamycin can lead

to hypocalcemia. Only the salmon-derived

product is available.

Biphosphonates

(etidronate,

pamidronate)

Etidronate: 7.5 mg/kg IV daily × 3 days

over at least 2 hours.

Maintenance: 20 mg/kg/day PO.

Pamidronate: 60 to 90 mg IV for 4 hours ×

1. Repeat in 7 days PRN.

Inhibits osteoclast reabsorption in

malignancy state. Efficacy 75% to 100%.

Onset 48 hours. Duration, days.

Concomitant hydration is imperative. Do not

use in renal failure. Adverse effects: ↑

phosphorus, ↑ SCr, N/V (oral).

Zoledronic acid Doses: 4 mg IV administration for 15

minutes.

Potent effect on bone resorption. Preferred

bisphosphonate for hypercalcemia of

malignancy. May have promising effects on

skeletal complications secondary to bone

metastasis.

Gallium nitrate

phosphate

100–200 mg/m

2

/day infused IV over 24

hours for 5 days (depending on severity of

hypercalcemia).

If calcium levels return to normal before 5

days, therapy may be discontinued.

IV PO−4

not recommended

PO PO−4

gradually titrate to 30 to 60

mmol/day (1–3 g/day in divided doses).

Inhibits bone resorption. Patients should be

well hydrated during therapy. A urine

output of ∼2 L/day should be maintained

owing to risk for nephrotoxicity (10%).

Inhibits bone resorption; soft tissue

calcification. IV onset 24 hours but not drug

of choice. Oral agents used for chronic

therapy. Contraindicated in renal failure.

Corticosteroids Prednisone: 60–80 mg/day

Hydrocortisone: 5 mg/kg/day IV × 2–3

days.

Impair GI absorption and bone resorption.

Onset several days. Best in patients with

multiple myeloma, vitamin D intoxication,

granulomatous conditions. Can be used in

HF, renal failure.

Indomethacin 75–150 mg/day. Reports of efficacy are mixed.

GI, gastrointestinal; HF, heart failure; IM, intramuscularly; IV, intravenously; NS, normal saline; N/V, nausea and

vomiting; PO, orally; PRN, as needed; SC, subcutaneously; SCr, serum creatinine.

p. 589

p. 590

Calcitonin

Calcitonin can be used when saline hydration and furosemide diuresis fail to lower

serum calcium concentration adequately or when their use is contraindicated.

Calcitonin reduces serum calcium concentration by inhibiting osteoclastic bone

resorption. It may also increase the renal excretion of calcium and phosphorus. Only

the salmon-derived calcitonin product is available in the United States.

The serum calcium concentration is often reduced several hours after calcitonin is

administered, and the response may last approximately 6 to 8 hours. The drug is

relatively nontoxic compared with organic phosphates and may be used in patients

with dehydration, HF, or renal failure.

189 Nausea, vomiting, diarrhea, and facial

flushing are the more common side effects; soreness and inflammation at the injection

site may also be seen.

184 Because of the potential for developing a hypersensitivity

reaction to salmon calcitonin, the manufacturer recommends skin testing with 1

international unit of the salmon calcitonin before the first dose. As seen in A.C.,

tolerance to the hypocalcemic effect of calcitonin can develop after 24 to 72 hours of

therapy. This “escape phenomenon” may be secondary to the altered responsiveness

of the hormone receptors and might be prevented by concurrent use of

corticosteroids.

190 After long-term therapy, antibodies may develop as well.

The dosage of salmon calcitonin is 4 international units/kg given SC or

intramuscularly every 12 hours; the maximal dosage is 8 international units/kg every

6 hours. The hypocalcemic response is often limited, and serum calcium

concentration seldom drops to the normal range.

191

Bisphosphonates

Bisphosphonates are synthetic analogs of pyrophosphate that form stable bonds that

are resistant to phosphatase degradation during osteoclast-mediated bone

mineralization and resorption. The compounds adsorb to the hydroxyapatite crystals

of the bone, inhibiting their growth and dissolution. In addition, the compounds may

have a direct effect on osteoclasts. The two distinct pharmacologic classes of

bisphosphonates that exist have different mechanisms of action. Etidronate, which

does not contain any nitrogen atom, is metabolized to cytotoxic, nonhydrolyzable

ATP analogs. In contrast, nitrogen-containing bisphosphonates, such as pamidronate

and zoledronic acid, inhibit the prenylation of proteins and have potent inhibitory

effects on osteoclast-mediated bone resorption.

192

In addition, they induce apoptosis

of osteoclasts as well as certain tumor cells. Further antitumor activities may be

mediated through their inhibitory effect on angiogenesis, stimulation of the γ-T-cell

fraction in blood, and reduction of cancer cells’ adherence to bone matrix. At

present, etidronate, pamidronate, and zoledronic acid are approved in the United

States for the treatment of hypercalcemia secondary to malignancy.

Etidronate

Etidronate is administered in doses of 7.5 mg/kg for 3 consecutive days by IV

infusion over the course of 2 to 4 hours. Response may be seen after 1 to 2 days, and

normocalcemia is expected to be attained in most patients, with response sustained

for greater than 10 days.

193 Because of the inconvenient dosing schedule as well as

variability in its duration of action, other bisphosphonates are now preferred for the

treatment of hypercalcemia of malignancy. In addition, etidronate may inhibit bone

mineralization, a property not shared by other bisphosphonates.