Disclosures: Elizabeth Shane, MD Nothing to disclose. James R Berenson, MD Grant/Research/Clinical Trial Support: Celgene; Onyx; Millennium; Novartis; AMGEN [myeloma (bisphosphonates)]. Speaker's Bureau: Celgene; Onyx; Millennium; Novartis; AMGEN [myeloma (bisphosphonates)]. Consultant/Advisory Boards: Celgene; Onyx; Millennium; Novartis; AMGEN [myeloma (bisphosphonates)]. Clifford J Rosen, MD Nothing to disclose. Jean E Mulder, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
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 concentrations".)
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 [1-3].
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.
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 [1,2,4]:
●Volume expansion with 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. (See 'Saline hydration' below.)
In the absence of renal failure or heart failure, loop diuretic therapy to directly increase calcium excretion is not recommended because of potential complications and the availability of drugs that inhibit bone resorption, which is primarily responsible for the hypercalcemia.
●Administration of salmon calcitonin (4 international units/kg) and repeat measurement of serum calcium in several hours. If a hypocalcemic response is noted, then the patient is calcitonin-sensitive and the calcitonin can be repeated every 6 to 12 hours (4 to 8 international units/kg). We typically administer calcitonin (along with a bisphosphonate) in patients with calcium >14 mg/dL who are also symptomatic. (See 'Calcitonin' below.)
●The concurrent administration of zoledronic acid (ZA; 4 mg intravenously [IV] over 15 minutes) or pamidronate (60 to 90 mg over two hours), preferably ZA, because it is superior to pamidronate in reversing hypercalcemia related to malignancy. (See 'Bisphosphonates' below.)
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 IV 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.
For patients with severe, symptomatic hypercalcemia of malignancy that is refractory to ZA, denosumab (initial dose 60 mg subcutaneously, with repeat dosing based upon response) is an alternative option. (See 'Denosumab' below.)
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, or in those with severe hypercalcemia complicated by renal failure. (See 'Dialysis' below.)
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:
●Hyperparathyroidism is the most common outpatient cause of mild hypercalcemia. The treatment is typically directed at correcting the hyperparathyroidism or monitoring for complications of primary hyperparathyroidism. (See "Primary hyperparathyroidism: Management".)
●Patients with lymphoma, sarcoidosis, or other granulomatous causes of hypercalcemia have enhanced intestinal calcium absorption due to increased endogenous calcitriol production. The major modalities of therapy are a low calcium diet, corticosteroids, and treatment of the underlying disease. (See "Hypercalcemia in granulomatous diseases".)
●Hypercalcemia due to ingestion of calcitriol as treatment for hypoparathyroidism, or for the hypocalcemia and hyperparathyroidism of renal failure, usually lasts only one to two days because of the relatively short biologic half-life of calcitriol. Thus, stopping the calcitriol, increasing salt and fluid intake, or perhaps hydrating with IV saline may be the only therapy that is needed.
●Hypercalcemia is typically not treated in patients with familial hypocalciuric hypercalcemia because the elevation in serum calcium is typically mild and produces few if any symptoms. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
SALINE HYDRATION — Initial therapy of severe hypercalcemia includes the simultaneous administration of saline, calcitonin, and a bisphosphonate (see 'Severe hypercalcemia' above). 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 [8,9]:
●The availability of drugs such as the bisphosphonates and calcitonin that inhibit bone resorption, which is primarily responsible for the hypercalcemia.
●The requirement for careful monitoring because of the potential fluid and electrolyte complications resulting from a massive saline infusion and furosemide-induced diuresis such as hypokalemia, hypomagnesemia, and volume depletion if the diuretic-induced losses are not replaced.
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 [10,11]. 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) [1,4,13,14]. 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 [1,11,15,16]. 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 — Among the currently available agents for the treatment of malignancy-associated hypercalcemia (pamidronate, zoledronic acid [ZA], ibandronate, clodronate, and etidronate), intravenous (IV) 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).
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 [1,17,19-24]. 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 [24-26]. 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' above.)
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".)
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'.)
Zoledronic acid — ZA is considered by many to be 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 available in many countries 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.)
Pamidronate — A number of observational studies and some randomized trials have demonstrated the efficacy of IV 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 [1,5,21,28-36].
Early trials showed pamidronate (60 mg over 24 hours) was more effective in ameliorating hypercalcemia of malignancy than IV 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 [22,34].
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.
IV 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 [37-39] (see "Hypercalcemia of malignancy", section on 'PTH-related protein'). Such patients may have a better response to ZA.
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 [40,41]. 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 four 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. The inconvenience of prolonged IV treatment and the relatively weak potency of etidronate have diminished its utility, and it is not generally recommended unless other bisphosphonates are not available .
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. 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. (See "The use of bisphosphonates in patients with multiple myeloma", section on 'Oral bisphosphonates' and "Overview of the use of osteoclast inhibitors in early breast cancer".)
Side effects and precautions — Although IV 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 [44,45]. 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 antiresorptive agents in patients with advanced malignancy" and "The use of bisphosphonates in postmenopausal women with osteoporosis", 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 [48,49]. However, we suggest caution when using IV 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".)
Denosumab — There are an increasing number of case reports and case series of denosumab for the management of hypercalcemia of malignancy, particularly in patients with persistent hypercalcemia despite bisphosphonates [50-52]. In one such series, 33 patients with hypercalcemia of malignancy with persistently elevated serum calcium levels corrected for albumin >12.5 mg/dL (3.1 mmol/L) after treatment with bisphosphonates were treated with denosumab 120 mg subcutaneously weekly for four weeks and then monthly thereafter. Within 10 days, 21 patients (64 percent) had serum calciums <11.5 mg/dL (2.9 mmol/L) . These preliminary data suggest that denosumab may be considered for patients with zoledronic acid (ZA)-refractory hypercalcemia. Clinical trials comparing ZA and denosumab in this setting are warranted.
Denosumab, unlike bisphosphonates, is not cleared by the kidney, and as a consequence there is no restriction of its use in patients with chronic kidney disease, for whom bisphosphonates are used with caution or contraindicated (see 'Dosing in renal impairment' above). In case reports of patients with multiple myeloma, hypercalcemia, and severe renal impairment (serum creatinine 2.5 to 5.7 mg/dL), denosumab improved serum calcium within two to four days, and in one case was associated with improvement in renal function [54,55]. Thus, denosumab may have a role in the treatment of hypercalcemia complicated by marked renal impairment or renal failure. However, the optimal dose of denosumab in the setting of renal impairment is uncertain. In trials of denosumab for osteoporosis, patients with chronic kidney disease were at higher risk for hypocalcemia following denosumab administration than patients with normal renal function (see "Denosumab for osteoporosis"). In a case series of denosumab for the treatment of hypercalcemia in patients with multiple myeloma and renal impairment, a single dose of denosumab (60 mg) in one patient resulted in prolonged hypocalcemia requiring intravenous (IV) calcium supplementation . It may be prudent to begin with a lower dose initially (0.3 mg/kg), with a second dose administered if the goal calcium is not achieved within approximately one week . It is also prudent to measure serum 25-hydroxyvitamin D (25[OH]D) levels, as patients with vitamin D deficiency may be more likely to develop hypocalcemia after denosumab administration. While awaiting the results of the serum 25(OH)D level, one could consider repleting with one or two days of vitamin D, 50,000 international units daily. If the patient is vitamin D deficient, it may help prevent hypocalcemia, and if they are vitamin D replete, the supplementation can be stopped.
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 "Primary hyperparathyroidism: Management".)
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 "Primary hyperparathyroidism: Management", 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 .
SUMMARY AND RECOMMENDATIONS
●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 diuretic and lithium carbonate therapy, volume depletion, prolonged bed rest or inactivity, and a high calcium diet (>1000 mg/day). (See 'Preferred approach' above.)
●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, an acute rise to these levels may cause gastrointestinal side effects and changes in sensorium, which requires treatment as described for severe hypercalcemia. (See 'Moderate hypercalcemia' above.)
●Patients with more severe (calcium >14 mg/dL [3.5 mmol/L]) or symptomatic hypercalcemia are usually dehydrated and require saline hydration as initial therapy. A reasonable regimen 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. (See 'Severe hypercalcemia' above and 'Saline hydration' above.)
●In patients with hypercalcemia receiving saline hydration, we suggest not routinely using a loop diuretic (Grade 2C). However, in individuals with renal insufficiency or heart failure, careful monitoring and judicious use of loop diuretics may be required to prevent fluid overload. (See 'Saline hydration' above.)
●For immediate short-term management of hypercalcemia, we suggest administration of calcitonin (in addition to saline hydration) only in patients with calcium >14 mg/dL (3.5 mmol/L) who are also symptomatic (Grade 2B). (See 'Severe hypercalcemia' above and 'Calcitonin' above.)
●For longer-term control of hypercalcemia in patients with more severe (calcium >14 mg/dL) or symptomatic hypercalcemia due to excessive bone resorption, we suggest the addition of a bisphosphonate rather than denosumab (Grade 2B). (See 'Severe hypercalcemia' above and 'Bisphosphonates' above.)
Denosumab is an option for patients with hypercalcemia that is refractory to zoledronic acid (ZA) or in whom bisphosphonates are contraindicated due to severe renal impairment. (See 'Denosumab' above.)
●Glucocorticoids are effective in treating hypercalcemia due to some lymphomas, sarcoid, or other granulomatous diseases. (See 'Glucocorticoids' above.)
●Dialysis is generally reserved for those with severe hypercalcemia. (See 'Severe hypercalcemia' above.)
- Bilezikian JP. Clinical review 51: Management of hypercalcemia. J Clin Endocrinol Metab 1993; 77:1445.
- Bilezikian JP. Management of acute hypercalcemia. N Engl J Med 1992; 326:1196.
- Maier JD, Levine SN. Hypercalcemia in the Intensive Care Unit: A Review of Pathophysiology, Diagnosis, and Modern Therapy. J Intensive Care Med 2015; 30:235.
- Fatemi S, Singer FR, Rude RK. Effect of salmon calcitonin and etidronate on hypercalcemia of malignancy. Calcif Tissue Int 1992; 50:107.
- Selby PL, Davies M, Marks JS, Mawer EB. Vitamin D intoxication causes hypercalcaemia by increased bone resorption which responds to pamidronate. Clin Endocrinol (Oxf) 1995; 43:531.
- Hosking DJ, Cowley A, Bucknall CA. Rehydration in the treatment of severe hypercalcaemia. Q J Med 1981; 50:473.
- Suki WN, Yium JJ, Von Minden M, et al. Acute treatment of hypercalcemia with furosemide. N Engl J Med 1970; 283:836.
- Body JJ. Hypercalcemia of malignancy. Semin Nephrol 2004; 24:48.
- LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Ann Intern Med 2008; 149:259.
- Austin LA, Heath H 3rd. Calcitonin: physiology and pathophysiology. N Engl J Med 1981; 304:269.
- Deftos LJ, First BP. Calcitonin as a drug. Ann Intern Med 1981; 95:192.
- Dumon JC, Magritte A, Body JJ. Nasal human calcitonin for tumor-induced hypercalcemia. Calcif Tissue Int 1992; 51:18.
- Wisneski LA. Salmon calcitonin in the acute management of hypercalcemia. Calcif Tissue Int 1990; 46 Suppl:S26.
- Vaughn CB, Vaitkevicius VK. The effects of calcitonin in hypercalcemia in patients with malignancy. Cancer 1974; 34:1268.
- Ljunghall S. Use of clodronate and calcitonin in hypercalcemia due to malignancy. Recent Results Cancer Res 1989; 116:40.
- Chevallier B, Peyron R, Basuyau JP, et al. [Human calcitonin in neoplastic hypercalcemia. Results of a prospective randomized trial]. Presse Med 1988; 17:2375.
- Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001; 19:558.
- Carano A, Teitelbaum SL, Konsek JD, et al. Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. J Clin Invest 1990; 85:456.
- Ryzen E, Martodam RR, Troxell M, et al. Intravenous etidronate in the management of malignant hypercalcemia. Arch Intern Med 1985; 145:449.
- Singer FR, Ritch PS, Lad TE, et al. Treatment of hypercalcemia of malignancy with intravenous etidronate. A controlled, multicenter study. The Hypercalcemia Study Group. Arch Intern Med 1991; 151:471.
- Gucalp R, Ritch P, Wiernik PH, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol 1992; 10:134.
- Gucalp R, Theriault R, Gill I, et al. Treatment of cancer-associated hypercalcemia. Double-blind comparison of rapid and slow intravenous infusion regimens of pamidronate disodium and saline alone. Arch Intern Med 1994; 154:1935.
- Rizzoli R, Thiébaud D, Bundred N, et al. Serum parathyroid hormone-related protein levels and response to bisphosphonate treatment in hypercalcemia of malignancy. J Clin Endocrinol Metab 1999; 84:3545.
- Berenson JR. Treatment of hypercalcemia of malignancy with bisphosphonates. Semin Oncol 2002; 29:12.
- Body JJ, Bartl R, Burckhardt P, et al. Current use of bisphosphonates in oncology. International Bone and Cancer Study Group. J Clin Oncol 1998; 16:3890.
- Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 2005; 352:373.
- Schwartz LM, Woloshin S. Lost in transmission--FDA drug information that never reaches clinicians. N Engl J Med 2009; 361:1717.
- Massagli TL, Cardenas DD. Immobilization hypercalcemia treatment with pamidronate disodium after spinal cord injury. Arch Phys Med Rehabil 1999; 80:998.
- Jansson S, Tisell LE, Lindstedt G, Lundberg PA. Disodium pamidronate in the preoperative treatment of hypercalcemia in patients with primary hyperparathyroidism. Surgery 1991; 110:480.
- Mark S. Hypercalcaemia in an immobilised patient with pneumonia. Br J Clin Pract 1995; 49:327.
- McIntyre HD, Cameron DP, Urquhart SM, Davies WE. Immobilization hypercalcaemia responding to intravenous pamidronate sodium therapy. Postgrad Med J 1989; 65:244.
- Gibbs CJ, Peacock M. Hypercalcaemia due to sarcoidosis corrects with bisphosphonate treatment. Postgrad Med J 1986; 62:937.
- Ralston SH, Gallacher SJ, Patel U, et al. Comparison of three intravenous bisphosphonates in cancer-associated hypercalcaemia. Lancet 1989; 2:1180.
- Sawyer N, Newstead C, Drummond A, Cunningham J. Fast (4-h) or slow (24-h) infusions of pamidronate disodium (aminohydroxypropylidene diphosphonate (APD)) as single shot treatment of hypercalcaemia. Bone Miner 1990; 9:121.
- Nussbaum SR, Younger J, Vandepol CJ, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med 1993; 95:297.
- Wimalawansa SJ. Optimal frequency of administration of pamidronate in patients with hypercalcaemia of malignancy. Clin Endocrinol (Oxf) 1994; 41:591.
- Gurney H, Grill V, Martin TJ. Parathyroid hormone-related protein and response to pamidronate in tumour-induced hypercalcaemia. Lancet 1993; 341:1611.
- Walls J, Ratcliffe WA, Howell A, Bundred NJ. Response to intravenous bisphosphonate therapy in hypercalcaemic patients with and without bone metastases: the role of parathyroid hormone-related protein. Br J Cancer 1994; 70:169.
- Wimalawansa SJ. Significance of plasma PTH-rp in patients with hypercalcemia of malignancy treated with bisphosphonate. Cancer 1994; 73:2223.
- Ralston SH, Thiébaud D, Herrmann Z, et al. Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia. Br J Cancer 1997; 75:295.
- Pecherstorfer M, Herrmann Z, Body JJ, et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. J Clin Oncol 1996; 14:268.
- Pecherstorfer M, Steinhauer EU, Rizzoli R, et al. Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate. Support Care Cancer 2003; 11:539.
- O'Rourke NP, McCloskey EV, Vasikaran S, et al. Effective treatment of malignant hypercalcaemia with a single intravenous infusion of clodronate. Br J Cancer 1993; 67:560.
- Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol 2006; 17:897.
- Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf 1999; 21:389.
- Henrich D, Hoffmann M, Uppenkamp M, Bergner R. Ibandronate for the treatment of hypercalcemia or nephrocalcinosis in patients with multiple myeloma and acute renal failure: Case reports. Acta Haematol 2006; 116:165.
- Machado CE, Flombaum CD. Safety of pamidronate in patients with renal failure and hypercalcemia. Clin Nephrol 1996; 45:175.
- Trimarchi H, Lombi F, Forrester M, et al. Disodium pamidronate for treating severe hypercalcemia in a hemodialysis patient. Nat Clin Pract Nephrol 2006; 2:459.
- Davenport A, Goel S, Mackenzie JC. Treatment of hypercalcaemia with pamidronate in patients with end stage renal failure. Scand J Urol Nephrol 1993; 27:447.
- Dietzek A, Connelly K, Cotugno M, et al. Denosumab in hypercalcemia of malignancy: a case series. J Oncol Pharm Pract 2015; 21:143.
- Karuppiah D, Thanabalasingham G, Shine B, et al. Refractory hypercalcaemia secondary to parathyroid carcinoma: response to high-dose denosumab. Eur J Endocrinol 2014; 171:K1.
- Adhikaree J, Newby Y, Sundar S. Denosumab should be the treatment of choice for bisphosphonate refractory hypercalcaemia of malignancy. BMJ Case Rep 2014; 2014.
- Hu MI, Glezerman IG, Leboulleux S, et al. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab 2014; 99:3144.
- Cicci JD, Buie L, Bates J, van Deventer H. Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction. Clin Lymphoma Myeloma Leuk 2014; 14:e207.
- Bech A, de Boer H. Denosumab for tumor-induced hypercalcemia complicated by renal failure. Ann Intern Med 2012; 156:906.
- Koo WS, Jeon DS, Ahn SJ, et al. Calcium-free hemodialysis for the management of hypercalcemia. Nephron 1996; 72:424.
- Leehey DJ, Ing TS. Correction of hypercalcemia and hypophosphatemia by hemodialysis using a conventional, calcium-containing dialysis solution enriched with phosphorus. Am J Kidney Dis 1997; 29:288.