Treatment of hypercalcemia

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".)

●(See "Etiology of hypercalcemia".)

●(See "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".)

PREFERRED APPROACH — 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 'Mild hypercalcemia' below.)

●Patients with a serum calcium of 12 to 14 mg/dL (3 to 3.5 mmol/L) may not require immediate treatment, because that degree of hypercalcemia may be well tolerated chronically (see 'Moderate hypercalcemia' below). However, an acute rise to these concentrations may cause marked changes in sensorium, which requires more aggressive measures. (See 'Severe hypercalcemia' below.)

●Patients with a serum calcium concentration >14 mg/dL (3.5 mmol/L) require more aggressive treatment, regardless of symptoms. (See 'Severe hypercalcemia' below.)

The reference range for ionized calcium varies with the assay, and therefore, the ionized calcium thresholds for intervention depend on the assay. In an ionized calcium assay with a normal range of 4.8 to 5.6 mg/dL (1.2 to 1.4 mmol/L), mild, moderate, and severe hypercalcemia may be defined as follows [4]:

●Mild – Ionized calcium 5.6 to 8 mg/dL (1.4 to 2 mmol/L)

●Moderate – Ionized calcium 8 to 10 mg/dL (2 to 2.5 mmol/L)

●Severe – Ionized calcium 10 to 12 mg/dL (2.5 to 3 mmol/L)

MILD HYPERCALCEMIA — Patients with asymptomatic or mildly symptomatic hypercalcemia (total albumin-corrected 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

●Lithium carbonate

●Volume depletion

●Prolonged bed rest or inactivity

●A high-calcium diet (>1000 mg/day)

●Calcium supplements

●Vitamin D supplements in excess of 800 international units/day

●Multivitamins containing calcium

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 'Disease-specific approach' below.)

MODERATE HYPERCALCEMIA — Asymptomatic or mildly symptomatic individuals with chronic moderate hypercalcemia (total albumin-corrected 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. (See 'Severe hypercalcemia' below.)

SEVERE HYPERCALCEMIA — Patients with total albumin-corrected calcium >14 mg/dL (>3.5 mmol/L) require more aggressive therapy. As described immediately above, patients with an acute rise in serum calcium to more moderate levels who have changes in sensorium (eg, lethargy, stupor) also require aggressive therapy.

Initial therapy of severe hypercalcemia includes the simultaneous administration of intravenous (IV) isotonic saline, subcutaneous calcitonin, and a bisphosphonate (typically, IV zoledronic acid) (table 1) [1,2,5]. The administration of calcitonin plus saline hydration 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 and provide a more sustained effect, thereby maintaining control of the hypercalcemia.

Volume expansion with isotonic saline — Most patients presenting with severe hypercalcemia have marked intravascular volume depletion. Hypovolemia exacerbates hypercalcemia by impairing the renal clearance of calcium [6]. Isotonic saline for 24 to 48 hours corrects possible volume depletion due to hypercalcemia-induced urinary salt wasting and, in some cases, vomiting [7,8].

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.

In the absence of renal failure or heart failure, loop diuretic therapy to directly increase calcium excretion is not recommended [9], because of the availability of drugs (eg, bisphosphonates) that inhibit bone resorption, which is primarily responsible for the hypercalcemia, as well as the potential for fluid and electrolyte complications (eg, hypokalemia, hypomagnesemia) and volume depletion resulting from a massive saline infusion and furosemide-induced diuresis.

However, saline therapy can lead to fluid overload in patients who cannot excrete the administered salt because of impaired renal function or heart failure. In individuals with renal insufficiency or heart failure, careful monitoring and judicious use of loop diuretics (after intravascular volume has been repleted) may be required to prevent fluid overload.

Saline therapy rarely normalizes the serum calcium concentration in patients with more than mild hypercalcemia [6]. Concurrent treatment with bisphosphonates with or without calcitonin is typically required to treat moderate to severe hypercalcemia.

Calcitonin — Calcitonin should be administered intramuscularly or subcutaneously; nasal administration of calcitonin is not efficacious for treatment of hypercalcemia [10]. The initial dose is 4 units/kg. The serum calcium is repeated in four to six hours. If a hypocalcemic response is noted, then the patient is calcitonin sensitive and the calcitonin can be repeated every 12 hours for a total duration of 24 to 48 hours. If the response is not satisfactory, the dose may be increased to 8 units/kg every 6 to 12 hours (total duration of therapy 24 to 48 hours) (table 1).

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 [1,11-13]. Because of its limited duration of effect, calcitonin is most useful in symptomatic patients with calcium >14 mg/dL (3.5 mmol/L), when combined with hydration and bisphosphonates (or denosumab, in bisphosphonate-refractory patients).

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 [11,14]. 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 [1,5,15,16]. Thus, it is useful in combination with hydration for the initial management of severe hypercalcemia.

Choice of antiresorptive agent: Bisphosphonates — 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 an IV bisphosphonate rather than denosumab. Bisphosphonates are relatively inexpensive, nontoxic compounds with a long track record of safety and efficacy for the treatment of hypercalcemia. They are usually the preferred agents for management of hypercalcemia due to excessive bone resorption from a variety of causes, including malignancy-related hypercalcemia [17]. 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 (table 1).

Randomized trials show evidence of bisphosphonate efficacy compared with saline alone for the treatment hypercalcemia of malignancy [18-22]. There are no randomized trials specifically evaluating denosumab for hypercalcemia of malignancy. In an observational study in patients with hypercalcemia of malignancy, there was no difference between denosumab and IV bisphosphonates in the response rate by day 7 (89 and 86 percent, respectively) [23]. The risk of subsequent hypocalcemia is lower with bisphosphonates than with denosumab.

For patients in whom bisphosphonates are contraindicated (eg, due to severe kidney impairment, bisphosphonate allergy), or for patients with hypercalcemia refractory to zoledronic acid, denosumab is an option and can be administered concurrently with calcitonin and saline hydration. (See 'Bisphosphonate contraindications or refractory hypercalcemia' below.)

Our preference for an IV bisphosphonate differs from that of the 2023 Endocrine Society Clinical Practice Guidelines, which suggest denosumab over bisphosphonates for initial therapy of hypercalcemia of malignancy [24]. The Endocrine Society based their suggestion on indirect evidence from randomized trials evaluating outcomes other than hypercalcemia (eg, skeletal-related events, mortality) in patients with cancer and bone metastases but without hypercalcemia [22,25-28]. Osteolytic metastases account for a smaller proportion of cases of hypercalcemia of malignancy than humoral hypercalcemia of malignancy (20 versus almost 80 percent) [29]. (See "Hypercalcemia of malignancy: Mechanisms", section on 'Mechanisms of hypercalcemia'.)

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 "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)

Pretreatment considerations — We review vitamin D and creatinine levels prior to administering bisphosphonates. These laboratory tests are usually obtained as part of the evaluation for hypercalcemia. (See "Diagnostic approach to hypercalcemia", section on 'Laboratory evaluation'.)

●Vitamin D – An elevated serum concentration of 25-hydroxyvitamin D is indicative of vitamin D intoxication due to the ingestion of either vitamin D or calcidiol itself. However, some patients with hypercalcemia due to another etiology (eg, hypercalcemia of malignancy) may have hypercalcemia and concomitant vitamin D deficiency. Such patients are more likely to develop hypocalcemia after treatment with zoledronic acid (or denosumab). If the 25-hydroxyvitamin D level is less than 20 ng/dL, vitamin D should be cautiously replaced (eg, 400 to 800 international units daily). (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Special populations'.)

●Creatinine – If renal function is impaired, the bisphosphonate should be infused at a slower rate, and in some cases, at a reduced dose. (See 'Dosing in renal impairment' below.)

Choice of drug and dosing — Zoledronic acid (4 mg IV over 15 minutes) is preferred over pamidronate (60 to 90 mg over 2 hours) because it is superior to pamidronate in reversing hypercalcemia related to malignancy [20]. Ibandronate and clodronate are less commonly used options. Alendronate and risedronate are potent, third-generation bisphosphonates that can be given orally; however, neither is used for the treatment of severe or acute hypercalcemia.

●Zoledronic acid – In a pooled analysis of two separate phase III trials involving a total of 275 patients with tumor-induced hypercalcemia, a single dose of zoledronic acid (either 4 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) [20]. In addition, the median duration of serum calcium control was longer for those receiving zoledronic acid (32 to 43 versus 18 days).

Although renal events were reported more frequently with zoledronic acid 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 zoledronic acid 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) [30]. (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 [1,21,31-40].

Early trials showed pamidronate (60 mg over 24 hours) was more effective in ameliorating hypercalcemia of malignancy than IV etidronate (70 versus 41 percent) [21] or clodronate [37]. Subsequent trials showed that shorter infusion times (two to four hours) were safe and effective, maintaining normocalcemia for two or more weeks [19,38].

The maximal calcium response occurs at 90 mg IV [39]. However, some 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 [41-43]. Such patients may have a better response to zoledronic acid.

●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 [44,45]. 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 [45].

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 [46]. 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 – Clodronate, a first-generation bisphosphonate, is a relatively weak inhibitor of bone resorption compared with the newer agents. Oral clodronate is 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. An IV bisphosphonate is often preferred at the onset of therapy, with oral clodronate being used for maintenance therapy. 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 [47]. (See "Use of osteoclast inhibitors in early breast cancer" and "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Other bisphosphonates'.)

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, and impaired renal function, including proteinuria [48-51]. (See 'Pretreatment considerations' above.)

Repetitive use of bisphosphonates has been associated with risk of developing osteonecrosis of the jaw and atypical femur fractures (in patients who require long-term therapy) [48,52]. These side effects associated with long-term therapy may be of limited relevance in the management of acute hypercalcemia where the use of these drugs may be not repeated on a regular basis. Adverse effects of bisphosphonates are reviewed in more detail separately; the incidence varies somewhat with the indication for use, due in part to the higher doses used in cancer patients compared with those with osteoporosis. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Risks specific to intravenous bisphosphonates' and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Risks shared by oral and IV bisphosphonates'.)

Dosing in renal impairment — In patients with impaired renal function (creatinine >4.5 mg/dL), we suggest caution when using IV bisphosphonates to treat hypercalcemia. Adequate hydration with saline and treatment with a reduced dose and/or slower infusion rate (2 to 4 mg zoledronic acid over 30 to 60 minutes, 30 to 45 mg pamidronate over 4 hours, 2 mg ibandronate over 1 hour) may minimize risk. The renal tubular toxicity is related to the rate of infusion.

As mentioned in the preceding section, bisphosphonates have potential nephrotoxicity [51]. However, in clinical trials of zoledronic acid 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 [20]. In addition, there are case reports of successful use of ibandronate and pamidronate for patients with renal failure and multiple myeloma [53], renal insufficiency (creatinine ≥1.5 mg/dL [133 micromol/L]) [54], and in hemodialysis patients with severe hypercalcemia [55,56].

Bisphosphonate contraindications or refractory hypercalcemia — For patients in whom bisphosphonates are contraindicated (eg, due to severe renal impairment, bisphosphonate allergy), or in patients with hypercalcemia refractory to zoledronic acid, denosumab is an option and can be administered concurrently with calcitonin and saline hydration. (See "Denosumab for osteoporosis", section on 'Mechanism of action'.)

Hemodialysis should be considered 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 are hemodynamically stable and in those with severe hypercalcemia complicated by renal insufficiency or heart failure, in whom hydration cannot be safely administered [57].

●Denosumab dosing

•Contraindications to bisphosphonates – For patients in whom bisphosphonates are contraindicated, we treat with an initial dose of 60 mg subcutaneously. Careful monitoring of serum calcium levels is necessary in patients with renal insufficiency because there is a higher risk of hypocalcemia with denosumab than with bisphosphonates [58]. Patients with vitamin D deficiency may be more likely to develop hypocalcemia after denosumab administration. If the serum 25-hydroxyvitamin D returns below normal, we begin cautious treatment with vitamin D (eg, 400 to 800 international units daily). (See 'Pretreatment considerations' above.)

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 hypercalcemia of malignancy and severe renal impairment (serum creatinine 2.5 to 5.7 mg/dL), denosumab 60 mg subcutaneously improved serum calcium within two to four days and, in one case, was associated with improvement in renal function [58-60]. Thus, denosumab may have a role in the treatment of hypercalcemia associated with marked renal impairment or renal failure. However, since the renal failure may be due to acute hypercalcemia, avoiding IV bisphosphonates may be unwarranted, especially as denosumab is associated with a higher risk of hypocalcemia than bisphosphonates. (See "Denosumab for osteoporosis", section on 'Safety information'.)

•Refractory hypercalcemia – For patients with hypercalcemia refractory to zoledronic acid, we treat with an initial dose of 120 mg subcutaneously. If after approximately two to seven days there is little improvement, we administer another dose of 120 mg. Thereafter, if the underlying cause of hypercalcemia persists (eg, malignancy), long-term therapy (monthly) is required. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Denosumab'.)

There are an increasing number of case reports and case series of denosumab for the management of chronic hypercalcemia of malignancy, particularly in patients with persistent hypercalcemia after treatment with bisphosphonates [59,61,62]. In one study, 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 three to four weeks and then monthly thereafter. Within 10 days, 21 patients (64 percent) had serum calcium levels <11.5 mg/dL (2.9 mmol/L) [63].

●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 [64].

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 [65].

PREVENTING RECURRENCE — 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 (IV) zoledronic acid or pamidronate every three to four weeks as part of their treatment to prevent skeletal complications. As a result, recurrent hypercalcemia will be prevented. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)

●In patients with renal insufficiency and history of hypercalcemia, calcium intake should be limited to 1000 mg per day (total diet plus any supplements). Excessive vitamin D supplements (ergocalciferol or cholecalciferol) should be avoided. (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease", section on 'Initial treatment'.)

●In patients with normal renal function and history of hypercalcemia, excessive amounts of calcium and vitamin D supplements should also be avoided.

DISEASE-SPECIFIC APPROACH — The modalities described above apply in varying degrees to patients with all causes of hypercalcemia. The treatment of specific disorders is discussed in detail in other topic reviews. Summarized briefly:

●Hyperparathyroidism – Hyperparathyroidism is the most common outpatient cause of mild hypercalcemia. The treatment is typically parathyroidectomy or monitoring for complications of primary hyperparathyroidism. (See "Primary hyperparathyroidism: Management".)

Parathyroid carcinoma is a rare cause of hyperparathyroidism but may cause more severe hypercalcemia than most parathyroid adenomas. Patients typically present with marked hypercalcemia and very high parathyroid hormone concentrations or a neck mass. The primary treatment of parathyroid carcinoma is surgery. When the tumor is no longer curable by surgical intervention, treatment becomes focused on the control of hypercalcemia with medical therapy, which can include bisphosphonates, calcimimetic agents, or denosumab. (See "Parathyroid carcinoma", section on 'Treatment'.)

The calcimimetic agent cinacalcet 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 'Treatment' and "Primary hyperparathyroidism: Management", section on 'Severe hypercalcemia' and "Management of secondary hyperparathyroidism in adult patients on dialysis", section on 'Calcimimetics'.)

●Granulomatous diseases – 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, glucocorticoids, and treatment of the underlying disease. 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 and by reducing intestinal calcium absorption. (See "Hypercalcemia in granulomatous diseases".)

●Hypervitaminosis D – Hypercalcemia associated with excess administration or ingestion of vitamin D is primarily due to increased absorption of dietary calcium. It is sometimes seen in combination with excess calcium intake and in individuals with renal insufficiency. High doses of vitamin D also have been shown to increase bone resorption, by activating osteoclasts. Vitamin D actions on the distal nephron will increase the tubular reabsorption of calcium, which further worsens hypercalcemia.

•Calcitriol – 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 intravenous (IV) saline may be the only therapy that is needed.

•Vitamin D – Hypercalcemia caused by vitamin D or calcidiol lasts longer, so that more aggressive therapy such as glucocorticoids (eg, prednisone in a dose of 20 to 40 mg/day) and zoledronic acid or pamidronate may be necessary [35].

●Familial hypocalciuric hypercalcemia – Hypercalcemia is typically not treated in patients with familial hypocalciuric hypercalcemia (FHH), 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".)

SUMMARY AND RECOMMENDATIONS

●General principles – 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. (See 'Preferred approach' above.)

●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, calcium and/or vitamin D supplements, and a high-calcium diet (>1000 mg/day). (See 'Mild hypercalcemia' above.)

●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, an acute rise to these levels may cause changes in sensorium, which requires treatment as described for severe hypercalcemia. (See 'Moderate hypercalcemia' above and 'Severe hypercalcemia' above.)

●Severe hypercalcemia – Patients with more severe (calcium >14 mg/dL [3.5 mmol/L]) or symptomatic (eg, lethargy, stupor) hypercalcemia require aggressive therapy. Initial therapy of severe hypercalcemia includes the simultaneous administration of intravenous (IV) isotonic saline, subcutaneous calcitonin, and a bisphosphonate (typically, IV zoledronic acid) (table 1).

•Isotonic saline – Most patients with severe hypercalcemia have marked intravascular volume depletion. Isotonic saline for 24 to 48 hours corrects volume depletion and enhances renal excretion of calcium. A reasonable initial rate is 200 to 300 mL/hour that is then adjusted to maintain the urine output at 100 to 150 mL/hour. 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 (after intravascular volume has been repleted) may be required to prevent fluid overload. (See 'Severe hypercalcemia' above.)

•Calcitonin – For immediate, short-term management of hypercalcemia in symptomatic patients (eg, lethargy, stupor) with calcium >14 mg/dL (3.5 mmol/L), we suggest administration of calcitonin (Grade 2C). Calcitonin is used in combination with saline hydration and bisphosphonates. The initial dose is 4 units/kg, administered subcutaneously or intramuscularly. (See 'Severe hypercalcemia' above and 'Calcitonin' above.)

•Bisphosphonates – 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 an IV bisphosphonate rather than denosumab (Grade 2C). Bisphosphonates have a long track record of safety and randomized trial evidence of efficacy for the treatment of hypercalcemia due to excessive bone resorption from a variety of causes, including malignancy-related hypercalcemia. (See 'Severe hypercalcemia' above and 'Choice of antiresorptive agent: Bisphosphonates' above.)

Among IV bisphosphonates, we suggest zoledronic acid (Grade 2B). The initial dose is 4 mg IV over 15 minutes. (See 'Choice of drug and dosing' above.)

•Refractory hypercalcemia or bisphosphonate contraindications – Denosumab is an option for patients with hypercalcemia that is refractory to zoledronic acid or in whom bisphosphonates are contraindicated due to severe renal impairment or bisphosphonate allergy. Careful monitoring of serum calcium levels is necessary in patients with renal impairment because there is a higher risk of hypocalcemia with denosumab than with bisphosphonates. Dialysis may be indicated in patients with severe malignancy-associated hypercalcemia and renal insufficiency or heart failure, in whom hydration cannot be safely administered. (See 'Bisphosphonate contraindications or refractory hypercalcemia' above.)