Signs and symptoms of hypercalcemia may be absent or subtle, except when calcium is significantly elevated or has increased rapidly. The diagnostic workup of hypercalcemia is usually straightforward (Figure 247-3) because two causes, primary hyperparathyroidism and malignancy-associated hypercalcemia, account for approximately 90% of cases. In addition, most individuals with primary hyperparathyroidism are asymptomatic and discovered on routine biochemical screening tests, while most individuals with malignancy-associated hypercalcemia have a known advanced malignancy at the time that hypercalcemia occurs. If the malignancy is not known, it is generally quickly apparent. When neither of these two etiologies is readily apparent, identification of the other potential etiologies requires a comprehensive history, physical examination, laboratory tests, and, occasionally, diagnostic imaging studies.
Presenting Symptoms and History
Many individuals with mild hypercalcemia (serum calcium level < 11 mg/dL) are asymptomatic, although some may report mild fatigue, vague changes in cognitive function, depression, or constipation. Symptomatic manifestations of hypercalcemia become more apparent when the serum calcium concentration is between 12 to 14 mg/dL. These symptoms include anorexia, nausea, weakness, and depressed mental status. As hypercalcemia may induce polyuria and nephrogenic diabetes insipidus, dehydration can occur should the compensatory polydipsia not be able to match urinary water losses. When serum calcium levels rise above 14 mg/dL, profound dehydration, renal dysfunction, and central nervous system changes, such as progressive lethargy, disorientation, and coma, may develop.
In addition to the absolute magnitude of the serum calcium elevation, the rate of increase in serum calcium also influences symptoms. Individuals who are chronically hypercalcemic may have relatively few symptoms, even with serum calcium values up to 15 to 16 mg/dL. In contrast, those whose calcium level has risen abruptly may have symptoms at much more modest calcium levels. Elderly or debilitated patients are more likely to be affected by hypercalcemia than younger individuals.
The medical record may contain clues to etiology. Prescription medications (Table 247-1), foods, and vitamin and nutritional supplements should be reviewed. A careful family history might uncover a familial endocrine condition. A history of family members with endocrine tumors of the pituitary or pancreas suggests multiple endocrine neoplasia type 1 syndrome (MEN-1). A family history of pheochromocytoma or medullary thyroid cancer is consistent with MEN-2 syndrome. Patients with sarcoidosis may have a history of unexplained fever, lymphadenopathy, skin rashes, or pulmonary symptoms. Bone pain suggests myeloma or other malignancies, although it may also be a nonspecific finding of hypercalcemia.
Table 247-1 Causes of Hypercalcemia |Favorite Table|Download (.pdf)
Table 247-1 Causes of Hypercalcemia
- Primary hyperparathyroidism
- Parathyroid adenoma
- Parathyroid hyperplasia
- Parathyroid carcinoma
- Tertiary hyperparathyroidism
- Familial hypocalciuric hypocalcemia
- Thiazide diuretics
- HHM: PTHrP mediated
- Squamous carcinoma of the lung, oropharynx, nasopharynx, larynx, and esophagus
- Gynecologic (cervical, ovarian)
- Urologic (renal, transitional cell of bladder)
- Pancreatic islet cell tumors
- T-cell lymphoma
- HHM: 1,25-(OH)2-D3 mediated
- Local osteolytic hypercalcemia
- Multiple myeloma
- Breast carcinoma metastatic to bone
- Vitamin D
- Vitamin A
- Thiazide diuretics
- Calcium-containing antacids (in milk-alkali syndrome)
- Granulomatous diseases
- Other conditions
- Factitious hypercalcemia (due to increased plasma protein levels)
- Acute renal failure
- Severe thyrotoxicosis
- Adrenal insufficiency
The physical examination is directed at identifying signs or symptoms of hypercalcemia. Evidence for dehydration such as orthostasis or dry mucous membranes may be present, although hypercalcemia has to be quite marked and prolonged for these physical findings to be appreciated. The physical examination is often normal in patients with hypercalcemia, especially if calcium levels are only modestly elevated. Rarely, severe and prolonged hypercalcemia may produce a visible horizontal deposit of calcium salts on the cornea, a finding called band keratopathy.
Effort should be made to identify signs of common causes of hypercalcemia, such as malignancy and primary hyperparathyroidism. The physical examination in primary hyperparathyroidism, like most hypercalcemic states, is usually not noteworthy. A mass is virtually never found in the neck, because enlarged parathyroid glands are still too small to be felt. However, when the serum calcium is markedly elevated, a neck mass may signify a parathyroid carcinoma. Symptomatic kidney stones might be accompanied by costovertebral tenderness. Enlarged lymph nodes suggest sarcoid, lymphoma, or metastatic carcinoma.
The first step in evaluating hypercalcemia is adjustment for serum albumin. If the corrected serum calcium is elevated, it should be repeated. Renal function should also be assessed, because hypercalcemia may develop or worsen in the setting of acute renal failure. If hypercalcemia is confirmed, the next step is measurement of serum PTH. The PTH level is the most important test for distinguishing between the two most common causes of hypercalcemia, primary hyperparathyroidism and malignancy-associated hypercalcemia (Table 247-1). The so-called “intact” immunochemiluminometric assay for PTH assay primarily measures the intact molecule, PTH(1-84), and a large circulating fragment that is foreshortened at the amino terminus, PTH(7-84). A more specific assay that measures only PTH(1-84), the “bio-intact” assay, is also available, but it has not shown any clear advantages over the older assay, which has been in clinical use for over 20 years. When the creatinine clearance falls below 60 mL/min, these assays may begin to show elevations in PTH due to the accumulation of inactive fragments, and also perhaps due to increased secretory activity of the parathyroids (secondary hyperparathyroidism).
When the parathyroid glands are functioning normally, hypercalcemia should suppress PTH levels. Hypercalcemia is said to be PTH-mediated if serum calcium is elevated, and the PTH level is high or inappropriately normal. In this latter situation, one is usually dealing with primary hyperparathyroidism, although familial hypocalciuric hypercalcemia (FHH) and medication-induced hypercalcemia, as from thiazide diuretics or lithium, can also be associated with elevated PTH levels. When PTH levels are appropriately suppressed in hypercalcemia, the differential diagnosis includes malignancy, granulomatous disease, medications, milk-alkali syndrome, thyrotoxicosis, and adrenal insufficiency.
Other recommended tests in the evaluation of hypercalcemia include serum electrolytes and 25-hydroxyvitamin D. Levels of 25-hydroxyvitamin D typically exceed 150 ng/mL in vitamin D toxicity due to excess intake. Levels this high cannot be achieved by sun exposure alone. High 1,25-(OH)2D levels may be seen in any granulomatous disease, particularly sarcoidosis or certain lymphomas. Inorganic phosphorus measurement may be helpful, as a low-normal serum phosphate is often seen in primary hyperparathyroidism, while high phosphate may be seen in vitamin D intoxication. An elevated serum creatinine may indicate dehydration, or true renal dysfunction due to renal deposition of calcium salts or other causes. An elevated alkaline phosphatase level suggests elevated bone turnover. This may be confirmed by a bone-specific alkaline phosphatase measurement, or other indices of bone turnover, such as serum osteocalcin, serum C-terminal collagen peptide measurement, or urinary N-terminal collagen peptide. Most forms of hypercalcemia are accompanied by hypercalciuria (24-hour urine calcium excretion > 4 mg/kg/24 h). However, in primary hyperparathyroidism, renal calcium excretion is lower than expected for the degree of hypercalcemia, because PTH conserves filtered calcium in the distal renal tubule.
Other diagnostic studies are dictated by clinical circumstances. A shorted QTc interval can be seen on the electrocardiogram, particularly if the hypercalcemia has occurred over a short period of time. Bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA) can be helpful. In primary hyperparathyroidism, there is a typical pattern of BMD with relative preservation of cancellous bone, as in the lumbar spine, and preferential reduction in cortical bone, as in the femoral neck and distal third of the radius. Abdominal imaging studies (CT or ultrasound) may identify renal stones or nephrocalcinosis. Serum and urine protein electrophoresis should be obtained if myeloma is suspected. Skeletal radiographs may reveal lytic lesions of multiple myeloma or other malignancies. Skeletal radiographs in primary hyperparathyroidism may show subperiosteal bone resorption or brown tumors of bone, but are rarely needed for diagnosis at present.
Causes of PTH-Mediated Hypercalcemia
Elevation of both the serum calcium and PTH concentrations, in the absence of lithium use or low urinary calcium excretion as seen in familial hypocalciuric hypercalcemia, supports a diagnosis of primary hyperparathyroidism. In this condition, PTH levels are usually within 1.5 to 2.0 times above the upper limit of normal. Extremely high levels of PTH raise the specter of parathyroid carcinoma. Typically, primary hyperparathyroidism is associated with mild hypercalcemia, within 1 mg/dL above the upper limit of normal. The PTH level may be elevated, but may also fall in the upper portion of the normal range, which is inappropriate in hypercalcemia. Normocalcemic primary hyperparathyroidism is a new diagnostic entity applied to patients whose total and free serum calcium levels are normal, but in whom the PTH level is consistently elevated. In the absence of a secondary cause for elevated PTH levels, it is felt that these individuals have an early form of primary hyperparathyroidism.
Primary hyperparathyroidism is the most common cause of hypercalcemia in outpatients. The incidence of primary hyperparathyroidism is estimated to be approximately 21.6 per 100,000 person-years. The mean age at diagnosis is in the sixth decade of life, and there is a female-to-male ratio of 2:1. The clinical manifestations of primary hyperparathyroidism depend largely on the severity of the hypercalcemia. When primary hyperparathyroidism was first described more than 80 years ago, most patients presented with biochemically advanced disease, and overt radiographic abnormalities of bone (osteitis fibrosa cystica) or kidneys (nephrolithasis or nephrocalcinosis). Since the introduction more than 40 years ago of automated multichannel auto-analyzers for measuring serum chemistry, primary hyperparathyroidism is most often diagnosed by routine blood testing, well before the development of other signs or any symptoms. It also may be uncovered during the evaluation of osteoporosis or during the workup of renal stone disease. The most common clinical presentation today is mild asymptomatic hypercalcemia. In 75% to 80% of cases, a solitary, benign parathyroid adenoma is present. Hyperplasia involving multiple parathyroid glands is found in 15% to 20% of cases, and parathyroid carcinoma is present in less than 0.5%. On occasion, double adenomas are found. Patients with MEN-1 or MEN-2 usually have parathyroid hyperplasia involving all parathyroid glands.
Parathyroid surgery is always indicated in symptomatic primary hyperparathyroidism, unless there are medical contraindications. The role of parathyroid surgery in asymptomatic primary hyperparathyroidism is more controversial. According to the guidelines of the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism, indications for surgery in asymptomatic patients include a serum calcium > 1 mg/dL above the upper limit of normal; creatinine clearance < 60 mL/min; T-score < −2.5 at lumbar spine, hip, or distal third of the radius; and age < 50. Patients who do not meet these guidelines can be followed expectantly. Thiazide diuretics and lithium should be avoided. Dietary calcium should not be restricted, because such restriction may promote further elevation of PTH, and possibly have adverse effects on bone mass. In patients who are vitamin D deficient, cautious replacement of vitamin D is advised. Patients should maintain hydration. Bisphosphonates increase lumbar spine BMD in primary hyperparathyroidism, without a major effect on the serum calcium concentration. The calcimimetic, cinacalcet, reduces the serum calcium in primary hyperparathyroidism without having a major effect on BMD. Neither alendronate nor cinacalcet has been approved by the Food and Drug Administration (FDA) for use in primary hyperparathyroidism. Cinacalcet has been approved by the FDA for use in parathyroid cancer.
Lithium can change the set point for the calcium-sensing receptor on the parathyroid gland, such that a higher serum calcium concentration is needed to inhibit PTH secretion. This can lead to mild biochemical abnormalities, such as high levels of calcium and high-normal to elevated PTH levels, that mimic primary hyperparathyroidism, but do not require medical intervention.
Thiazide-associated hypercalcemia also occurs. Many patients with hypercalcemia on thiazides probably have primary hyperparathyroidism. When thiazide therapy is discontinued, the hypercalcemia often persists, and the diagnosis of primary hyperparathyroidism is made.
Familial Hypocalciuric Hypercalcemia
Familial hypocalciuric hypercalcemia, also known as benign familial hypercalcemia, is a rare genetic condition caused by inactivating mutations in the CaSR. This results in insensitivity of the parathyroid cell to ambient serum calcium, a higher set point for the extracellular ionized calcium concentration, and inappropriately normal to mildly elevated PTH levels. Patients with FHH have chronic asymptomatic hypercalcemia, associated with very low urinary calcium excretion. The relatively low urinary calcium excretion in FHH helps distinguish it from primary hyperparathyroidism, although low urinary calcium excretion may also occur in individuals with primary hyperparathyroidism. A family history of asymptomatic, stable mild hypercalcemia, especially in individuals younger than 40 years, is suggestive of FHH. Other evidence for FHH includes the presence of a very low urinary calcium to creatinine clearance ratio (< 0.01), or a history of family members who have undergone noncurative parathyroidectomy for presumed primary hyperparathyroidism. When FHH is suspected, further evaluation is necessary, such as screening of other family members for hypercalcemia. Genetic testing for FHH is available at select centers and may be appropriate in some cases. Sometimes it can be exceedingly difficult to distinguish FHH from primary hyperparathyroidism.
Conditions that are associated with low serum calcium are usually also associated with chronically elevated PTH levels, which is an appropriate physiological response. This is called secondary hyperparathyroidism. The rise in PTH may be sufficient to restore the serum calcium to normal, or calcium may remain low or in the low normal range. Secondary hyperparathyroidism is not a hypercalcemic state. Common causes of secondary hyperparathyroidism include vitamin D deficiency, intestinal malabsorption of calcium or vitamin D, renal-based hypercalciuria, severe nutritional calcium deficiency, and especially chronic renal insufficiency. Correction of the underlying cause usually returns serum PTH concentrations to normal. The return of the PTH to normal may be relatively rapid, if the inciting condition is of relatively recent onset, or it can be protracted, if the associated condition has been longstanding. In patients with prolonged secondary hyperparathyroidism, the reactive state can become semiautonomous, leading to hypercalcemia. This is known as tertiary hyperparathyroidism. It is most often seen in patients with poorly controlled chronic kidney disease. Tertiary hyperparathyroidism is usually associated with hyperplasia of multiple glands, but may also be caused by a parathyroid adenoma from a single clone of parathyroid cells.
Most patients with primary hyperparathyroidism have a serum calcium concentration below 11 mg/dL. The serum phosphate tends to be in the low normal range (2.5–3.2 mg/dL). A non-anion gap hyperchloremic acidosis from a PTH-induced defect in bicarbonate resorption is rarely seen. Urinary calcium excretion tends to be in the upper range of normal. Nevertheless, hypercalciuria in primary hyperparathyroidism does not always predispose to renal stones, an interesting observation in view of the fact that in euparathyroid subjects, hypercalciuria is a risk factor for kidney stones. Bone turnover markers tend to be at the upper limit or normal, but occasionally can be frankly elevated.
Once the diagnosis of primary hyperparathyroidism is made, it should be determined whether or not the patient meets guidelines for parathyroidectomy. If the clinical situation is appropriate, consideration should be given to the possibility of one of the MEN syndromes, particularly if the patient is young, or has a personal or family history of a related endocrinopathy. A diagnosis of MEN-1 or MEN-2 should prompt a search for multiple parathyroid gland disease.
Causes of PTH-Independent Hypercalcemia
If the serum calcium concentration is elevated but the PTH level is appropriately suppressed, the patient has hypercalcemia due to causes other than hyperparathyroidism, or PTH-independent hypercalcemia. Cancer is the most common cause. When PTH is suppressed and the patient does not have a malignancy, diagnostic considerations extend to other causes of PTH-independent hypercalcemia, including thyrotoxicosis, vitamin D intoxication, sarcoidosis, immobilization, Addison disease, and various drugs and supplements.
In hypercalcemia of malignancy, calcium is usually moderately or severely elevated, and PTH is low or undetectable. Significant dehydration and generalized debility are usually evident, along with other cancer-related symptoms. Usually, the diagnosis of malignancy has already been established when patients become hypercalcemic. Hypercalcemia of malignancy has two forms: humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia. HHM results from tumor production of a circulating factor with systemic effects on calcium metabolism, acting at the level of skeletal calcium release, renal calcium handling, or intestinal calcium absorption. The usual cause of HHM is parathyroid hormone-related protein (PTHrP). Normally, PTHrP serves as a paracrine factor in tissues such as bone, skin, breast, uterus, placenta, and blood vessels, where it is involved in cellular calcium handling, smooth muscle contraction, and growth and development. The amino terminus of the PTHrP peptide is closely homologous with native PTH, and they share a common receptor. When PTHrP circulates at supraphysiologic concentrations, it induces metabolic effects similar to PTH, activating osteoclasts to resorb bone, decreasing renal calcium output, and increasing renal phosphate clearance.
Tumors that produce HHM by secreting PTHrP are typically squamous cell carcinomas, arising from the lung, esophagus, head and neck, or cervix. Other tumors that may elaborate PTHrP include adenocarcinoma of the breast or ovary, renal carcinoma, transitional cell carcinoma of the bladder, islet cell tumors of the pancreas, T-cell lymphoma, and pheochromocytoma. As tumors that produce PTHrP do so in relatively small amounts, the syndrome typically develops in patients with a large tumor burden. It is therefore unusual for HHM to be the presenting feature of a cancer. The diagnosis may be confirmed by a commercially available radioimmunoassay for PTHrP. Care should be taken to ensure that blood for PTHrP levels is drawn and handled correctly to avoid spurious low results. Rarely, HHM is caused by the unregulated production of 1,25-dihyroxyvitamin D, usually by B-cell lymphomas, or other mediators that interfere with calcium homeostasis.
The other major mechanism of malignancy-associated hypercalcemia is the direct invasion of bone by tumor, associated with lytic destruction and calcium release. While this was formerly thought to be a mechanical process, it now appears to be driven by the local elaboration of cytokines leading to osteoclast-mediated bone resorption. In local osteolytic hypercalcemia, PTHrP and calcitriol are within normal limits. Bony metastases are usually obvious on imaging studies. The classic tumor associated with this syndrome is multiple myeloma, although breast cancer and certain lymphomas may also be responsible. Local osteolytic hypercalcemia may be perpetuated by a positive feedback loop, whereby factors produced by bone promote the growth and survival of metastases, and the tumor induces osteoclasts to produce factors promoting tumor growth, bone resorption, and hypercalcemia. Interruption of this positive feedback loop is the rationale for the use of bisphosphonates in the treatment of multiple myeloma.
PTH-independent hypercalcemia also occurs in sarcoidosis, tuberculosis, and other granulomatous diseases. Macrophages in the granuloma convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, via an unregulated 1-α hydroxylase enzyme. 25-hydroxyvitamin D levels are typically not elevated. When serum 25-hydroxyvitamin D levels are elevated, excessive vitamin D intake becomes the more likely etiology. Endocrine conditions that may occasionally lead to hypercalcemia include severe hyperthyroidism, which stimulates bone resorption, and Addison disease, where volume depletion reduces calcium clearance and control of calcium absorption is mitigated by glucocorticoid deficiency.
Immobilization is a stimulus for bone resorption and may increase serum calcium levels, particularly in bedbound hospitalized patients. This is usually seen in persons with high bone turnover, such as adolescents and patients with unrecognized hyperparathyroidism or Paget disease of bone. Drugs and dietary supplements may be associated with hypercalcemia. Vitamin D intoxication and excessive intake of vitamin A, which activates bone resorption, are occasional culprits. Thiazide diuretics may cause hypercalcemia due to enhanced renal retention of calcium. In many cases, this develops in individuals with underlying mild primary hyperparathyroidism.
If investigation of these diagnoses proves fruitless, the rare possibility of occult malignancy should be considered, especially if PTHrP is elevated. Further imaging studies would then be needed for tumor localization, including a plain chest radiograph or a computed tomographic scan of the chest to rule out lung malignancy. If these are unrevealing, consideration should be given to otolaryngoscopic examination, esophagoscopy, or CT of the abdomen, followed by radiographic or endoscopic evaluation of the genitourinary tract if necessary.
- In the early 20th century, the Chicago physician Bertram Sippy grew rich and nationally famous because of his “Sippy diet” for peptic ulcers—a regimen of milk, cream, eggs, and cereal 3 times a day, punctuated by aggressive antacid therapy with hourly sodium bicarbonate and magnesium hydroxide. This may or may not have been very effective for ulcers, but some patients certainly did develop severe hypercalcemia, in what became known as milk-alkali syndrome. Patients developed a metabolic alkalosis, which favors renal reabsorption of calcium, and the resulting hypercalcemia would produce renal vasoconstriction and a drop in GFR, leading to further increases in serum calcium. Up to one-third of these patients had chronic renal failure. Milk-alkali syndrome became rare with the introduction of H2-blockers and proton pump inhibitors for peptic ulcer disease. However, a similar disorder is seen increasingly in postmenopausal women who consume large amounts of supplemental calcium carbonate and vitamin D for the prevention of osteoporosis. Pregnant or bulimic women with metabolic alkalosis from emesis who are taking calcium and vitamin D are also at risk. It has been suggested that the disorder be renamed the calcium-alkali syndrome. Treatment is volume expansion with saline, cessation of alkali intake, and limitation of calcium supplementation.
Treatment of Hypercalcemia
Hypercalcemia that requires urgent management is usually due to malignancy, rather than a parathyroid disorder. However, primary hyperparathyroidism occasionally can present with severe hypercalcemia against a background of mild, asymptomatic disease. Urgent management of hypercalcemia includes aggressive rehydration, bisphosphonate therapy to decrease bone resorption, and elimination of contributing factors, such as calcium or vitamin D supplements, thiazide diuretic therapy, and immobilization. Second-line therapies include calcitonin to increase renal calcium excretion, and glucocorticoids to diminish intestinal calcium absorption.
Most patients with emergent hypercalcemia are dehydrated due to anorexia and polyuria. Intravascular volume should be aggressively restored with intravenous normal saline, with an initial bolus of 500 to 1000 mL, followed by maintenance fluids at a rate of 200 mL per hour or more, depending on the patient's renal function and cardiac reserve (Table 247-2). Typically, patients require 3 to 4 L for rehydration in the first 24 hours. Patients need careful monitoring of fluid intake and output to prevent fluid overload. Normal saline dilutes serum calcium, and facilitates calciuresis by increasing glomerular filtration rate and the amount of filtered calcium, and decreasing tubular calcium reabsorption. Administration of furosemide or other loop diuretics to further promote calcium excretion may be considered after intravascular volume is restored. However, the use of loop diuretics to treat hypercalcemia has not been studied in randomized controlled trials, and may not be superior to vigorous use of saline alone. Thiazide diuretics should be avoided, as they enhance calcium reabsorption.
Table 247-2 Treatment of Hypercalcemia |Favorite Table|Download (.pdf)
Table 247-2 Treatment of Hypercalcemia
- Intravenous fluids
- Loop diuretic
- Furosemide intravenous (titrated to response, if necessary)
- Pamidronate (30–90 mg IV)
- Zoledronic acid (4 mg IV)
- Calcitonin (4 IU/kg SC every 12 hours)
- Prednisone (20–100 mg orally daily or equivalent)—in selected situations
- Plicamycin (15–25 μg/kg IV)—no longer used
- Gallium nitrate (200 mg/m2/day infusion over 5 days)—no longer used
- Other interventions
- Decrease calcium and vitamin D intake (if causative)
- Maintain adequate oral hydration
- Primary therapy directed at tumor
The major target of medical management in hypercalcemia is osteoclast-mediated bone resorption. In severe hypercalcemia, a pharmacologic approach to inhibit osteoclast action is warranted. First line therapy is an intravenous bisphosphonate, such as pamidronate or zoledronic acid. Pamidronate is administered in a dosage of 30 to 90 mg intravenously over several hours. Serum calcium levels should decline in 24 to 48 hours, although the maximal effect may not be evident for several days. Zoledronic acid is given at a dosage of 4 mg intravenously over no less than 15 minutes. It appears to have a greater potency and a longer duration of action than pamidronate. The need for repeat treatment with either pamidronate or zoledronic acid depends on the aggressiveness of the underlying malignancy. The first dose of intravenous bisphophonates may be associated with fever, headache, arthralgias, and myalgias. Intravenous bisphosphonates should be used with caution in the setting of renal dysfunction. Dose reduction of zoledronic acid is recommended for creatinine clearance below 60 ml/min, and its use in patients with creatinine clearance below 30 ml/min is not recommended. Pamidronate may be used with caution in patients with renal insufficiency, but the dose should be infused slowly, over 4 to 6 hours. The newer bisphophonate ibandronate may be associated with a lower risk of nephrotoxicity than other intravenous agents.
Other Approaches to Emergent Hypercalcemia
The action of intravenous bisphosphonate is not immediate. If there is a need to reduce the serum calcium quickly, the combined use of subcutaneous calcitonin (4 IU /kg every 12 hours) and intravenous bisphosphonate has become popular. Although rather weak, calcitonin acts rapidly, probably by facilitating urinary calcium excretion. The combination of a short-acting and long-acting anticalcemic can be very effective in managing these patients. In severe or refractory cases, hemodialysis against a low-calcium bath may be employed. Plicamycin and gallium nitrate are treatments of largely historical interest, because of either toxicities (plicamycin) or ineffectiveness (gallium nitrate).
In multiple myeloma, vitamin D intoxication, or disorders associated with the ectopic production of 1,25-dihydroxyvitamin D, such as sarcoidosis and lymphoma, the use of glucocorticoids can be very effective. Glucocorticoids impair vitamin D action, inhibit intestinal calcium absorption, and may have a direct antitumor effect.
Addressing the Underlying Disorder
Successful management of acute hypercalcemia also requires treating the underlying etiology. When primary hyperparathyroidism is the cause, parathyroid surgery is indicated when the patient is stable enough to undergo the procedure. In malignancy-associated hypercalcemia, surgery, radiotherapy or chemotherapy may be appropriate. However, because hypercalcemia is often an end-stage complication of malignancy, such interventions may not be warranted.
The discharge plan should include short-term repeat measurements of calcium, creatinine, and other electrolytes in the outpatient setting, and a long-range plan should be in place to prevent recurrence of hypercalcemia, such as repeat bisphosphonate dosing when needed. Patients should be told to seek prompt care if recurrent symptoms of hypercalcemia develop, such as nausea, vomiting, malaise, and polyuria. Patients should be educated as to their underlying condition, particularly if this is a malignancy, in which case outpatient oncology follow-up should be arranged. Consideration should be given to hospice care if hypercalcemia arises in the setting of advanced malignancy with poor prognosis.