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Pamidronate

Pamidronate is more potent than etidronate as an inhibitor of bone resorption, but it

has negligible effect on bone mineralization. For moderate hypercalcemia (albumincorrected serum calcium concentration of 12.0–13.5 mg/dL), a single dose of 60 to

90 mg of pamidronate is commonly infused over the course of 3 to 4 hours. For

severe hypercalcemia (albumin-corrected serum calcium concentration >13.5

mg/dL), the dose is 90 mg. The advantages of pamidronate are that it requires only a

single dose and produces a superior response compared with three doses of

etidronate.

194

If the hypercalcemia recurs, the etidronate or the pamidronate regimen may be

repeated after an interval of greater than or equal to 7 days. Etidronate (20 mg/kg/day

by mouth) may be given to prolong the normocalcemic duration, but nausea and

vomiting are common with the oral therapy. Long-term treatment may result in

osteomalacia; however, the limited life expectancy of most patients may diminish the

significance of this adverse effect.

Etidronate use has resulted in renal failure,

195 which probably is caused by the

formation of bisphosphonate–calcium complexes in the serum.

196 Because

pamidronate requires a lower molar concentration to produce a comparable

hypocalcemic effect, it is less likely to impair renal function. In fact, pamidronate has

been given to a limited number of patients with end-stage renal disease without

adverse consequence.

196

Zoledronic Acid

Among the bisphosphonates approved for the treatment of hypercalcemia of

malignancy, zoledronic acid has the most potent effect on bone resorption. It is

superior to pamidronate with respect to the number of complete responses, time

needed to attain calcium normalization, and duration of effect.

197 Because 8-mg doses

are not superior to 4-mg dose, 4-mg doses are administered IV over the course of 15

minutes.

198 The drug is well tolerated at 4-mg doses. Zoledronic acid’s superior

efficacy and convenience of administration make it the preferred bisphosphonate for

hypercalcemia of malignancy. Emerging studies show that zoledronic acid may also

have promising effects in reducing skeletal complications secondary to bone

metastasis associated with breast cancer, prostate cancer, non–small cell lung

cancer, and multiple myeloma.

198

Gallium Nitrate

Gallium is a naturally occurring group IIIa heavy metal. In addition to its antitumor

activity and potential for use as a chemotherapeutic agent, it has been shown to be

effective in the treatment of moderate-to-severe hypercalcemia of malignancy.

Hypocalcemia is induced primarily via the inhibition of bone resorption and

reduction in urinary calcium excretion.

199 Several clinical studies have shown the

effectiveness of gallium nitrate in the treatment of cancer-related hypercalcemia

when compared with agents such as calcitonin and bisphosphonates.

199–203 The

recommended dose is 100 to 200 mg/m2

/day as a 24-hour continuous infusion for 5

days. Vigorous hydration is necessary to prevent nephrotoxicity. In general, its

clinical use is limited by the inconvenient method of administration, significant risk

of nephrotoxicity, and cost.

p. 590

p. 591

Phosphate

Inorganic phosphates lower the serum calcium concentration by inhibiting bone

resorption. They also promote the deposition of calcium salts in the bone and soft

tissue. If given orally, phosphate reduces intestinal calcium absorption by forming a

poorly soluble complex in the bowel lumen and also by decreasing the formation of

active vitamin D through enzyme inhibition.

204

When given IV, phosphate is very effective, but renal failure and extensive

extraskeletal calcifications are a concern. For these reasons, IV phosphate is not the

agent of choice for acute treatment of hypercalcemia.

Oral phosphate (1–3 g/day in divided doses) may be used for long-term

maintenance therapy, with the optimal dose determined by serum calcium

concentrations. Nausea, vomiting, and diarrhea are common problems, especially

when the daily dose exceeds 2 g. Soft tissue calcification is also a concern, and

hyperphosphatemia and hypocalcemia can occur if the dose is not titrated

appropriately. Phosphate therapy should not be given to patients with

hyperphosphatemia or renal failure because it can cause further deterioration of renal

function. Accumulation of the potassium and sodium salts in phosphate preparations

may also present a therapeutic problem in certain patients.

Corticosteroids

Several possible mechanisms exist that may explain the hypocalcemic effect of

corticosteroids. Vitamin D3–mediated intestinal calcium absorption may be

impaired

205 and the action of osteoclast-activating factor, which mediates bone

resorption in malignancy, may be inhibited. Corticosteroids may also have a direct

cytolytic effect on tumor cells and inhibit the synthesis of prostaglandins (see the

subsequent section, Prostaglandin Inhibitors). Prednisone in daily doses of 60–80 mg

is given initially, with subsequent dosage reduction based on the calcemic response.

Alternatively, hydrocortisone (5 mg/kg/day for 2–3 days) may be given. The

hypocalcemic effect will not be apparent for at least 1 to 2 days. Patients with

hematologic malignancies and lymphomas tend to have a better response than those

with solid tumors. Corticosteroids are also effective in treating hypercalcemia

associated with vitamin D intoxication,

205 sarcoidosis,

206 and other granulomatous

conditions. They are not generally used for long-term therapy because of their

potential for serious adverse reactions.

Prostaglandin Inhibitors

Because prostaglandins of the E series, especially PGE2

, may be responsible for

hypercalcemia associated with some malignancies, NSAIDs may be useful for a

select group of patients with hypercalcemia.

207 For example, indomethacin is

effective in lowering the serum calcium concentration in patients with renal cell

carcinoma but not in patients with other types of malignancy.

194

Indomethacin, 75 to

150 mg/day, can be tried in patients unresponsive to other therapy, especially when it

is used as part of palliative treatment for cancer pain.

PHOSPHORUS

Homeostasis

Phosphorus is found primarily in bone (85%) and soft tissue (14%); less than 1% of

the total body store resides in the ECF. Virtually, all of the “free” or active

phosphorus exists as phosphates in the plasma. Most clinical laboratories, however,

measure and express the concentrations of elemental phosphorus contained in the

phosphate molecules. Phosphate of 1 mmol contains 1 mmol of phosphorus, but 1

mmol of phosphate is 3 times the weight of 1 mmol of phosphorus. Therefore, it is

incorrect to equate a certain milligram weight of phosphorus as the same milligram

weight of phosphate. Of the total plasma phosphorus, 70% exists as the organic form

and 30% as the inorganic form. Organic phosphorus, primarily phospholipids and

small amounts of esters, is bound to proteins. About 85% of inorganic phosphorus, or

orthophosphate, is unbound or “free.” The relative amounts of the two

orthophosphate components, H2PO4

− and HPO4

2−

, vary with pH. At pH 7.40, the ratio

of the two species is 1:4, giving rise to a composite valence of 1.8 for the

orthophosphate. Serum phosphate concentrations reported by clinical laboratories

reflect only the inorganic portion of the total plasma phosphate. To avoid confusion

related to the pH effect on valence, phosphate concentrations are reported as mg/dL

or mmol/dL rather than mEq/volume.

The normal range of serum phosphate concentration in healthy adults is 2.5 to 4.5

mg/dL. The value is higher in children, possibly because of the increased amount of

growth hormone and the reduced amount of gonadal hormones.

208

In postmenopausal

women, the range is slightly higher; it is lower in older men. The serum phosphate

concentration is also affected by dietary intake. Phosphate-rich foods can transiently

increase the serum phosphate concentration. In contrast, glucose decreases the serum

phosphate concentration because of the flux of sugar and phosphate into cells and

because of the phosphorylation of glucose. Similarly, administration of insulin and

epinephrine decreases the serum phosphate concentration because of their effects on

glucose. The serum concentration of phosphate is reduced in alkalosis and increased

in acidosis.

209

A balanced diet contains 800 to 1,500 mg/day phosphorus. Both the organic and

inorganic forms of phosphorus are present in food substances. Most of the

phosphorus in milk is the organic form; the phosphorus in meat, vegetable, and other

nondairy sources represents organic forms bound to proteins, lipids, and sugars,

which usually are hydrolyzed before absorption.

210

In general, 60% to 65% of the

phosphorus ingested is absorbed, mostly in the duodenum and jejunum through an

energy-dependent, saturable, active process.

211 Phosphorus absorption is linearly

related to the dietary intake when the intake is 4 to 30 mg/kg/day. The amount of

phosphorus ingested probably is the most important factor in determining net

absorption. Phosphorus absorption is also stimulated during periods of increased

demand, such as active growth and pregnancy.

212

Increased intake of calcium and

magnesium and concurrent use of aluminum hydroxide antacids may reduce

phosphorus absorption owing to formation of a nonabsorbable complex.

213

In

addition, absorption is also affected by vitamin D, PTH, and calcitonin.

208

Renal phosphorus excretion depends on the dietary phosphorus intake. Normally,

greater than 85% of the filtered phosphate load is reabsorbed; however, the

fractional urinary excretion can vary from 0.2% to 20%. Renal phosphate excretion

is also affected by acid–base balance, ECF volume, and calcium and glucose

concentrations.

208

In addition, PTH, thyroid hormone, thyrocalcitonin, vitamin D,

insulin, glucocorticoid, and glucagon can also alter renal phosphate excretion.

7

Hypophosphatemia

ETIOLOGY

CASE 27-12

QUESTION 1: M.R., a 72-year-old woman, was admitted to the hospital with a 1-week history of increasing

malaise, confusion, and decreased activity. M.R. has a history of HF, hypertension, type 2 diabetes, and peptic

ulcer disease. She was receiving hydrochlorothiazide, aluminum–magnesium antacid, sucralfate, and insulin. She

is febrile and in significant respiratory distress. ABG results at admission were pH, 7.5; PO2

, 42 mm Hg; and

PCO2

,

p. 591

p. 592

20 mm Hg. Respiratory function continued to deteriorate, requiring intubation and mechanical ventilation. Serum

electrolyte concentrations were as follows:

Na, 128 mEq/L

K, 3.6 mEq/L

Cl, 96 mEq/L

CO2

, 23 mEq/L

Glucose, 320 mg/dL

Phosphorus, 0.9 mg/dL

What may have contributed to the low serum phosphorus concentration in M.R.?

Hypophosphatemia can develop as the result of a phosphorus deficiency or

secondary to a net flux of phosphorus out of the plasma compartment without a total

body deficit. Moderate hypophosphatemia is defined as a serum phosphorus

concentration of 1.0 to 2.5 mg/dL. A concentration of less than 1.0 mg/dL, as in M.R.,

is considered severe.

214 The extent of hypophosphatemia may not be assessed

accurately by a single plasma phosphorus concentration determination because of

diurnal variation.

215 Patients receiving large doses of mannitol may have

pseudohypophosphatemia owing to the binding of mannitol with molybdate, which is

used in the calorimetric assay for phosphorus.

216

Hypophosphatemia is commonly caused by conditions that impair intestinal

absorption, increase renal elimination, or shift phosphorus from the extracellular to

the intracellular compartments. Hypophosphatemia secondary to low dietary

phosphorus is exceedingly rare because phosphorus is ubiquitous.

208

In addition,

renal phosphorus excretion is reduced and intestinal phosphorus absorption is

increased to prevent a deficiency state.

217 Starvation in itself does not result in severe

hypophosphatemia because the phosphorus content in plasma and muscles is often

normal. Hypophosphatemia, however, can develop during refeeding with a highcalorie diet low in phosphorus. Therefore, hyperalimentation without phosphorus

supplementation is likely to cause severe hypophosphatemia.

218

Impaired phosphorus absorption secondary to malabsorptive conditions,

prolonged nasogastric suction, and protracted vomiting can also result in

hypophosphatemia. In M.R., the use of aluminum-containing and magnesiumcontaining antacids may further reduce phosphorus absorption. The antacids bind

with endogenous and exogenous phosphorus in the GI tract and cause severe

hypophosphatemia in patients with or without renal failure.

219

In addition, M.R. was

taking sucralfate, which contains aluminum and can bind phosphorus in the GI tract.

220

Similarly, iron preparations can bind phosphorus.

221

Hyperglycemia-induced osmotic diuresis and diuretic use may have increased the

renal loss of phosphorus in M.R. Other conditions associated with renal phosphorus

wasting include renal tubular acidosis, hyperparathyroidism, hypokalemia,

hypomagnesemia, and extracellular volume expansion.

208 None of these situations,

however, was evident in M.R. Shifting of phosphorus into the intracellular

compartment by glucose or insulin and profound respiratory alkalosis may also have

contributed to M.R.’s hypophosphatemic state.

222,223

CASE 27-12, QUESTION 2: What other conditions are commonly associated with hypophosphatemia?

Diabetic ketoacidosis, chronic alcoholism, chronic obstructive airway disease,

and extensive thermal burns are other conditions commonly associated with

hypophosphatemia.

224,225 They are characterized by a combination of factors that

result in phosphate loss and intracellular phosphate use. In patients with diabetic

ketoacidosis, metabolic acidosis enhances the movement of phosphate from the

intracellular compartment to plasma, whereas the concurrent osmotic diuresis

secondary to hyperglycemia increases the renal elimination of extracellular

phosphate.

226 The net result is a depletion of total body stores. Correction of the

acidosis and administration of insulin then promotes the rapid uptake of phosphorus

by tissues, and volume repletion dilutes the extracellular concentration. This

sequence of events can ultimately lead to severe hypophosphatemia. The

hypophosphatemia associated with chronic alcoholism and acute alcohol intoxication

is also thought to be related to several factors, including reduced intestinal

phosphorus absorption caused by vomiting, diarrhea, and antacid use; repeated

acidosis that results in increased urinary phosphate excretion; and a shift of

phosphorus into cells because of respiratory alkalosis. Renal phosphorus wasting can

also result from hypomagnesemia or as a direct effect of alcohol.

226

CLINICAL MANIFESTATIONS

CASE 27-12, QUESTION 3: What are the signs and symptoms associated with hypophosphatemia?

The clinical effects associated with chronic phosphorus depletion are often

insidious and gradual in onset. In contrast, a rapid decline in plasma phosphorus

concentrations results in sudden and serious organ dysfunction. Most of the effects

can be attributed to impaired cellular energy stores and tissue hypoxia secondary to

depletion of ATP or erythrocyte 2,3-diphosphoglycerate.

227 Severe

hypophosphatemia can result in generalized muscle weakness, confusion,

paresthesias, seizures, and coma. In addition, reduced cardiac contractility,

hypotension, respiratory failure, and rhabdomyolysis have been observed with acute

severe hypophosphatemia.

208 Chronic phosphorus depletion has been associated with

decreased mentation; muscle weakness; osteomalacia; rickets; anorexia; dysphagia;

cardiomyopathy; tachypnea; reduced sensitivity to insulin; and dysfunction of red

blood cells, white blood cells, and platelets. Renal function is altered, as manifested

by hypophosphaturia, hypercalciuria, hypermagnesuria, bicarbonaturia, and

glycosuria. M.R.’s decreased mentation, weakness, and respiratory failure are

consistent with severe hypophosphatemia.

TREATMENT

CASE 27-12, QUESTION 4: How can phosphate depletion be assessed? Outline a treatment regimen that

would effectively and safely correct the phosphorus deficit in M.R. How should her therapy be monitored?

Phosphorus resides primarily in the intracellular space; the amount in the ECF is

only a small percentage of the total body store. Because the patient’s pH, blood

glucose concentration, and insulin availability may affect phosphorus distribution, it

is difficult to determine the magnitude of the phosphorus deficit based on the serum

concentration alone. As discussed, a patient may have hypophosphatemia secondary

to a rapid shift of phosphorus into the intracellular space without a total body deficit.

The duration of the hypophosphatemia is often limited because it may be corrected by

renal phosphorus conservation and oral intake of phosphorus-containing foods. Aside

from serum phosphorus concentrations, urinary phosphorus excretion may be used to

further assess the phosphorus deficit. Typically, renal phosphorus excretion is

severely limited in patients with significant deficits. A phosphorus excretion of less

than 100 mg/day (fractional phosphorus excretion <10%) confirms appropriate renal

phosphorus conservation when the serum phosphorus

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p. 593

is less than 2 mg/dL. It also suggests a nonrenal etiology (e.g., impaired GI

absorption) or some type of internal redistribution (e.g., respiratory alkalosis).

228

Prophylactic supplementation should be used in situations that predictably increase

the risk for developing hypophosphatemia. These include patients who are receiving

total parenteral nutrition or large doses of antacids for an extended period, alcoholic

patients, and those with diabetic ketoacidosis.

The specific treatment of hypophosphatemia depends on the presence of signs and

symptoms, as well as the anticipated duration and severity of hypophosphatemia. In

an asymptomatic patient with mild hypophosphatemia (1.5–2.5 mg/dL), who has no

evidence of phosphorus depletion, phosphorus supplementation is generally not

necessary because the condition is usually self-limited.