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INTRODUCTION — Treatment for hypercalcemia should be aimed both at lowering the serum calcium concentration and, if possible, treating the underlying disease. Effective treatments reduce serum calcium by inhibiting bone resorption, increasing urinary calcium excretion, or decreasing intestinal calcium absorption (table 1). The optimal choice varies with the cause and severity of hypercalcemia.
The treatment of hypercalcemia will be reviewed here, with emphasis on the management of hypercalcemia in patients with malignant disease. The modalities described below apply in varying degrees to patients with other causes of hypercalcemia. The clinical manifestations, etiology, and diagnostic approach to hypercalcemia are discussed separately. (See "Clinical manifestations of hypercalcemia" and "Etiology of hypercalcemia" and "Diagnostic approach to hypercalcemia".)
INTERPRETATION OF SERUM CALCIUM — Calcium in serum is bound to proteins, principally albumin. As a result, total serum calcium concentrations in patients with low or high serum albumin levels may not accurately reflect the physiologically important ionized (or free) calcium concentration. As an example, in patients with hypoalbuminemia, total serum calcium concentration may be normal when serum ionized calcium is elevated.
Alternatively, patients with hyperalbuminemia due to severe volume depletion and rare patients with multiple myeloma, who have a calcium-binding paraprotein, have increased protein binding of calcium. This can cause an elevation in the serum total calcium concentration without any rise in the serum ionized calcium concentration. This phenomenon is called pseudohypercalcemia (or factitious hypercalcemia), since the patient has a normal ionized serum calcium concentration.
In patients with hypoalbuminemia or hyperalbuminemia, the measured serum calcium concentration should be corrected for the abnormality in albumin (calculator 1) or for standard units (calculator 2). If a laboratory known to measure ionized calcium reliably is available, some authorities prefer to measure the serum ionized calcium in this situation. (See "Relation between total and ionized serum calcium concentration".)
INDICATIONS FOR TREATMENT — Hypercalcemia may be associated with a spectrum of clinical manifestations, ranging from few or no symptoms in patients with mild chronic hypercalcemia to severe obtundation and coma. (See "Clinical manifestations of hypercalcemia".) The degree of hypercalcemia, along with the rate of rise of serum calcium concentration, often determines symptoms and the urgency of therapy. The therapeutic approach should reflect these differences [1,2].
Patients with asymptomatic or mildly symptomatic (eg, constipation) hypercalcemia (calcium <12 mg/dL [3 mmol/L]) do not require immediate treatment. (See 'Preferred approach' below.) Similarly, a serum calcium of 12 to 14 mg/dL (3 to 3.5 mmol/L) may be well-tolerated chronically, and may not require immediate treatment. However, an acute rise to these concentrations may cause marked changes in sensorium, which requires more aggressive measures. In addition, patients with a serum calcium concentration >14 mg/dL (3.5 mmol/L) require treatment, regardless of symptoms.
SALINE HYDRATION — Initial therapy of severe hypercalcemia includes the simultaneous administration of saline, calcitonin, and a bisphosphonate. (See 'Severe hypercalcemia' below.) Isotonic saline corrects possible volume depletion due to hypercalcemia-induced urinary salt wasting and, in some cases, vomiting. Hypovolemia exacerbates hypercalcemia by impairing the renal clearance of calcium (table 1) .
The rate of saline infusion depends upon several factors, including the severity of hypercalcemia, the age of the patient, and presence of comorbid conditions, particularly underlying cardiac or renal disease. A reasonable regimen, in the absence of edema, is the administration of isotonic saline at an initial rate of 200 to 300 mL/hour that is then adjusted to maintain the urine output at 100 to 150 mL/hour.
Saline therapy requires careful monitoring, since it can lead to fluid overload in patients who cannot excrete the administered salt because of impaired renal function, which can be induced by hypercalcemia or heart failure. The saline infusion should be stopped in patients who develop edema and a loop diuretic may be used as necessary.
Saline therapy rarely normalizes the serum calcium concentration in patients with more than mild hypercalcemia . In the past, administration of a loop diuretic was initiated routinely once fluid repletion had been achieved to further increase urinary calcium excretion. However, this practice was based upon an approach that involved intensive administration of furosemide (80 to 100 mg every one to two hours) with aggressive fluid hydration (10 liters daily) .
Saline therapy beyond that necessary to restore euvolemia has fallen out of favor for two reasons [5,6]:
CALCITONIN — Pharmacologic doses of calcitonin reduce the serum calcium concentration by increasing renal calcium excretion and, more importantly, by decreasing bone resorption via interference with osteoclast function [7,8]. Salmon calcitonin (4 international units/kg) is usually administered intramuscularly or subcutaneously every 12 hours; doses can be increased up to 6 to 8 international units/kg every six hours. Nasal application of calcitonin is not efficacious for treatment of hypercalcemia .
Calcitonin is safe and relatively nontoxic (other than mild nausea and the rare hypersensitivity reaction). Although a relatively weak agent, it works rapidly, lowering the serum calcium concentration by a maximum of 1 to 2 mg/dL (0.3 to 0.5 mmol/L) beginning within four to six hours (table 1) [1,10-12]. Thus, it is useful in combination with hydration for the initial management of severe hypercalcemia.
The efficacy of calcitonin is limited to the first 48 hours, even with repeated doses, indicating the development of tachyphylaxis, perhaps due to receptor downregulation [1,8,13,14]. Because of its limited duration of effect, calcitonin is most beneficial in symptomatic patients with calcium >14 mg/L (3.5 mmol/L), when combined with hydration and bisphosphonates. Calcitonin and hydration provide a rapid reduction in serum calcium concentration, while a bisphosphonate provides a more sustained effect.
BISPHOSPHONATES — The bisphosphonates are nonhydrolyzable analogs of inorganic pyrophosphate that adsorb to the surface of bone hydroxyapatite and inhibit calcium release by interfering with osteoclast-mediated bone resorption . They are effective in treating hypercalcemia resulting from excessive bone resorption of any cause (table 1). (See "Pharmacology of bisphosphonates".)
All of the bisphosphonates are relatively nontoxic compounds and they are more potent than calcitonin and saline for patients with moderate or severe hypercalcemia [1,16-22]. As a result, they have become the preferred agents for management of hypercalcemia due to excessive bone resorption from a variety of causes, including malignancy-related hypercalcemia [22-24]. Their maximum effect occurs in two to four days, so that they are usually given in conjunction with saline and/or calcitonin, which reduce calcium concentration more rapidly. (See 'Preferred approach' below.)
Although bisphosphonates are most commonly used to treat established hypercalcemia, they have also been given to prevent hypercalcemia and adverse skeletal events, particularly in patients with metastatic cancer to bone. The use of bisphosphonates to improve outcomes for patients with cancer is discussed separately. (See "Bisphosphonates and denosumab in patients with metastatic cancer".)
Among the currently available agents for the treatment of malignancy-associated hypercalcemia (pamidronate, zoledronic acid, ibandronate, clodronate, and etidronate), intravenous zoledronic acid (ZA) or pamidronate are our bisphosphonates of choice. ZA is favored by some because it is more potent than pamidronate  and can be administered over a shorter time period (15 minutes compared to two hours).
Repetitive IV use of bisphosphonates has been associated with risk of developing osteonecrosis of the jaw in patients with multiple myeloma or metastatic bone disease. Some data suggest a higher risk of osteonecrosis of the jaw following the repeated use of ZA. As a result, some groups favor use of pamidronate over ZA in particular cancer patients, such as those with multiple myeloma. However, osteonecrosis of the jaw is a complication of long-term, high dose IV bisphosphonate therapy. Therefore, concerns about the risk of osteonecrosis of the jaw are of limited relevance in the management of acute hypercalcemia. (See 'Side effects and precautions' below and "The use of bisphosphonates in patients with multiple myeloma", section on 'Choice of agent'.)
Pamidronate — A number of observational studies and some randomized trials have demonstrated the efficacy of intravenous pamidronate for the treatment of hypercalcemia due to excessive bone resorption from a variety of causes, including malignancy, acute primary hyperparathyroidism, immobilization, hypervitaminosis D, and sarcoidosis [1,18,25-34].
Early trials showed pamidronate (60 mg over 24 hours) was more effective in ameliorating hypercalcemia of malignancy than intravenous etidronate (70 percent versus 41 percent)  or clodronate . Subsequent trials showed that shorter infusion times (two to four hours) were safe and effective, maintaining normocalcemia for two or more weeks [19,32].
The maximal calcium response occurs at 90 mg IV . However, many clinicians vary the usual initial dose of pamidronate according to the degree of hypercalcemia: 60 mg if the serum calcium concentration is up to 13.5 mg/dL (3 to 3.4 mmol/L) and 90 mg for higher levels. Serum calcium concentrations begin to decrease in one or two days. Doses should not be repeated sooner than a minimum of seven days.
Intravenous pamidronate is well tolerated, with a low incidence of fever being the main side effect. A less favorable response may be seen in patients with humoral hypercalcemia of malignancy, a paraneoplastic syndrome typically resulting from autonomous production of parathyroid hormone-related protein (PTHrP) by the tumor [35-37]. (See "Hypercalcemia of malignancy", section on 'PTH-related protein'.) Such patients may have a better response to zoledronic acid.
Zoledronic acid — Zoledronic acid (ZA) is considered by many the agent of choice for malignancy-associated hypercalcemia because it is more potent and effective than pamidronate. Although it can be administered over a shorter time period (15 minutes as compared with two hours), which may be more convenient, this may not be as important in the setting of hypercalcemia since many of these patients require hospitalization. ZA is currently approved by the United States Food and Drug Administration for treatment of hypercalcemia of malignancy at a dose of 4 mg IV over at least 15 minutes.
In a pooled analysis of two separate phase III trials involving a total of 275 patients with tumor-induced hypercalcemia, a single dose of ZA (either 4 mg or 8 mg) normalized the corrected serum calcium concentration in 87 to 88 percent of patients, compared with only 70 percent of those receiving pamidronate (90 mg) . In addition, the median duration of serum calcium control was longer for those receiving ZA (32 to 43 versus 18 days).
Although renal events were reported more frequently with ZA than with pamidronate in trials evaluating chronic use of these drugs to treat patients with metastatic bone disease, there was no difference in the frequency of grade 3 or 4 renal toxicity with either drug. The efficacy of the 4 and 8 mg ZA doses were similar, but the 4 mg dose was recommended because there was greater renal toxicity with the 8 mg dose (5.2 versus 2.3 percent with 4 mg) and higher all-cause mortality (33 versus 19 percent) . (See 'Dosing in renal impairment' below.)
Ibandronate — Ibandronate effectively treats hypercalcemia of malignancy. In combined trials with over 320 patients, ibandronate doses of 2 mg IV administered over two hours normalized serum calcium in up to 67 percent of patients, and doses up to 6 mg were safe and well tolerated [39,40]. The frequency of response was significantly higher with 4 or 6 mg than with 2 mg (76 to 77 versus 50 percent), but the duration of response was not dose-dependent .
Ibandronate appears to be as effective as pamidronate. Ibandronate (2 or 4 mg IV) was directly compared with pamidronate (15 to 90 mg IV) in a randomized trial involving 72 patients with hypercalcemia of malignancy . The number of patients responding to both agents was similar (77 and 76 percent for ibandronate and pamidronate, respectively) but the median time until the serum calcium began to rise again was significantly longer with ibandronate (14 versus 4 days). However, four days is an unusually short duration of effect for pamidronate and may reflect inadequate dosing or the small size of the clinical trial.
Clodronate and etidronate — Clodronate and etidronate are first generation bisphosphonates that were introduced over 20 years ago. They are relatively weak inhibitors of bone resorption compared with the newer agents. Clodronate is widely available outside the United States.
In randomized trials of patients with multiple myeloma or metastatic breast cancer, the administration of oral clodronate to decrease skeletal complications was associated with fewer episodes of severe hypercalcemia. (See "Osteoclast inhibition in the management of bone metastases from breast cancer" and "The use of bisphosphonates in patients with multiple myeloma", section on 'Oral bisphosphonates'.)
However, the poor oral bioavailability of clodronate, the size of the tablets, and the need to take them on an empty stomach with nothing to eat for one hour afterward increases the risk of noncompliance . As a result, IV clodronate is often preferred at the onset of therapy , with oral clodronate being used for maintenance therapy.
When used for treatment of malignancy-associated hypercalcemia, etidronate must be given intravenously (7.5 mg/kg in 250 mL of saline over four hours) for at least three consecutive days [16-18]. Prolonging treatment to five days increases responsiveness from 60 percent to almost 100 percent of patients. Other effective treatment schedules include a single 24-hour infusion (30 mg/kg) or 4.3 mg/kg IV daily for seven consecutive days [43,44]. Serum calcium levels may not decrease until approximately four days after treatment is started.
Prolonged administration of etidronate has been associated with hyperphosphatemia due to increased tubular reabsorption of phosphate. The dose of etidronate should be reduced by 50 percent in patients with impaired renal function because it is excreted in the urine.
The inconvenience of prolonged intravenous treatment and the relatively weak potency has diminished the utility of etidronate, and it is not generally recommended unless other bisphosphonates are not available .
Side effects and precautions — Although intravenous bisphosphonates are generally well tolerated, side effects may include flu-like symptoms (fever, arthralgias, myalgia, fatigue, bone pain), ocular inflammation (uveitis), hypocalcemia, hypophosphatemia, impaired renal function, nephrotic syndrome, and osteonecrosis of the jaw [45,46]. These side effects are discussed in detail elsewhere; the incidence varies somewhat with the indication for use due in part to the higher doses used in cancer patients compared to those with osteoporosis. (See "Risks of therapy with bone modifying agents in patients with advanced malignancy" and "Bisphosphonates in the management of osteoporosis in postmenopausal women", section on 'Adverse effects'.)
Dosing in renal impairment — As mentioned in the preceding section, bisphosphonates have potential nephrotoxicity. A separate issue is dosing of bisphosphonates in patients with underlying renal disease.
In clinical trials of ZA for the treatment of hypercalcemia of malignancy, patients with serum creatinine concentrations as high as 4.5 mg/dL (400 micromol/L) were eligible for participation . In addition, there are case reports of successful use of ibandronate and pamidronate for patients with renal failure and multiple myeloma , renal insufficiency (creatinine ≥1.5 mg/dL [133 micromol/L]) , and in hemodialysis patients with severe hypercalcemia [49,50]. However, we suggest caution when using intravenous bisphosphonates to treat hypercalcemia in patients with impaired renal function (creatinine >4.5 mg/dL). Adequate hydration with saline and treatment with a reduced dose and/or slower infusion rate (4 mg ZA over 30 to 60 minutes, 30 to 45 mg pamidronate over four hours, 2 mg ibandronate over one hour) may minimize risk.
GLUCOCORTICOIDS — Increased absorption of dietary calcium is primarily, but not completely, responsible for the hypercalcemia associated with the excess administration or ingestion of vitamin D, or with the endogenous overproduction of calcitriol (1,25-dihydroxyvitamin D, the most active metabolite of vitamin D). Increased calcitriol production can occur in patients with chronic granulomatous diseases (eg, sarcoidosis) and in occasional patients with lymphoma. In such patients, glucocorticoids (eg, prednisone in a dose of 20 to 40 mg/day) will usually reduce serum calcium concentrations within two to five days by decreasing calcitriol production by the activated mononuclear cells in the lung and lymph nodes. (See "Hypercalcemia in granulomatous diseases".)
GALLIUM NITRATE — The calcium-lowering effects of gallium nitrate were initially discovered when hypocalcemia developed in patients undergoing gallium imaging who previously had normal serum calcium levels . Gallium inhibits osteoclastic bone resorption, in part via inhibition of an ATPase dependent proton pump on the osteoclast ruffled membrane, without being directly cytotoxic or acting as a metabolic toxin to bone cells . Gallium also inhibits PTH secretion from parathyroid cells in vitro .
Unlike bisphosphonates, gallium appears to be effective in both PTHrP-mediated, and non-PTHrP-mediated hypercalcemia [51,54-56]. Preliminary data from clinical trials indicated that it is more potent than etidronate, pamidronate, and calcitonin alone [54-56].
The efficacy of gallium was more rigorously examined in a trial of 64 patients with malignancy-associated hypercalcemia (serum calcium ≥12 mg/dL [3 mmol/L] after intravenous hydration) . Patients were randomly assigned to daily intravenous gallium nitrate (200 mg/m2) daily for five days or pamidronate (60 mg, or 90 mg if initial calcium ≥13.5 mg/dL [3.8 mmol/L]) for one day followed by four days of placebo infusions.
Normocalcemia (serum calcium ≤10.5 mg/dL [2.7 mmol/L]) was achieved within 10 days in 69 and 56 percent of the gallium and pamidronate treated patients, respectively, and the estimated duration of normocalcemia in responders was 14 and 10 days, respectively. The disadvantages of gallium include its potential for nephrotoxicity, and the need for continuous infusion over five days . Therefore, for the treatment of hypercalcemia due to excessive bone resorption, we prefer to use bisphosphonates rather than gallium nitrate.
Calcimimetics — Primary hyperparathyroidism is the most common outpatient cause of hypercalcemia. The elevation in serum calcium is usually mild and treatment is typically directed at correcting the hyperparathyroidism. (See "Management of primary hyperparathyroidism".)
However, a calcimimetic agent (only cinacalcet is currently available) reduces the serum calcium concentration in patients with severe hypercalcemia due to parathyroid carcinoma and in hemodialysis patients with an elevated calcium-phosphorous product and secondary hyperparathyroidism. Calcimimetics have also been evaluated in patients with primary hyperparathyroidism, but are not standard therapy. (See "Parathyroid carcinoma", section on 'Calcimimetics' and "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients", section on 'Calcimimetics' and "Management of primary hyperparathyroidism", section on 'Calcimimetics'.)
Dialysis — Hemodialysis with little or no calcium in the dialysis fluid and peritoneal dialysis (though it is slower) are both effective therapies for hypercalcemia, and are considered treatments of last resort. Dialysis may be indicated in patients with severe malignancy-associated hypercalcemia and renal insufficiency or heart failure, in whom hydration cannot be safely administered .
The use of hemodialysis for patients with hypercalcemia but without renal failure may require alterations in the composition of conventional dialysis solutions in order to avoid an exacerbation or induction of other metabolic abnormalities, particularly hypophosphatemia. As an example, hemodialysis with a dialysis solution enriched with phosphorus (final phosphorous concentration of 4 mg/dL) resulted in rapid correction of all abnormalities in one patient in whom medical therapy had failed to reverse hypercalcemia, mental status changes, and hypophosphatemia due to primary hyperparathyroidism .
Mild hypercalcemia — Patients with asymptomatic or mildly symptomatic hypercalcemia (calcium <12 mg/dL [3 mmol/L]) do not require immediate treatment. However, they should be advised to avoid factors that can aggravate hypercalcemia, including thiazide diuretics and lithium carbonate therapy, volume depletion, prolonged bed rest or inactivity, and a high calcium diet (>1000 mg/day). Adequate hydration (at least six to eight glasses of water per day) is recommended to minimize the risk of nephrolithiasis. Additional therapy depends mostly upon the cause of the hypercalcemia. (See 'Other' below.)
Moderate hypercalcemia — Asymptomatic or mildly symptomatic individuals with chronic moderate hypercalcemia (calcium between 12 and 14 mg/dL [3 to 3.5 mmol/L]) may not require immediate therapy. However, they should follow the same precautions described above for mild hypercalcemia.
It is important to note that an acute rise to these concentrations may cause marked changes in sensorium, which requires more aggressive therapy. In these patients, we typically treat with saline hydration and bisphosphonates, as described for severe hypercalcemia (below).
Severe hypercalcemia — Patients with calcium >14 mg/dL (3.5 mmol/L) require more aggressive therapy. The acute therapy of such patients consists of a three-pronged approach [1,2,11]:
The administration of calcitonin plus saline should result in substantial reduction in serum calcium concentrations within 12 to 48 hours. The bisphosphonate will be effective by the second to fourth day, thereby maintaining control of the hypercalcemia.
Follow-up therapy is aimed at preventing recurrence of hypercalcemia. In patients with hypercalcemia of malignancy, progressive hypercalcemia will inevitably accompany tumor progression, and therefore the underlying disease causing the hypercalcemia should be treated, if at all possible. Many patients with malignancy may also have metastatic bone disease and will receive intravenous ZA or pamidronate every three to four weeks as part of their treatment to prevent skeletal complications. As a result, recurrent hypercalcemia will be prevented.
Additional, more aggressive measures are necessary in the rare patient with very severe, symptomatic hypercalcemia. Hemodialysis should be considered, in addition to the above treatments, in patients who have serum calcium concentrations in the range of 18 to 20 mg/dL (4.5 to 5 mmol/L) and neurologic symptoms but a stable circulation.
Other — The modalities described above apply in varying degrees to patients with all causes of hypercalcemia. The treatment of some disorders is discussed in detail in other topic reviews. Summarized briefly:
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