Treatment Considerations for Hypercalcemia of Malignancy in Adults

US Pharm. 2025;50(5):HS6-HS12.

ABSTRACT: Calcium, an electrolyte, is involved in a number of metabolic processes and signaling pathways. Elevated levels of calcium can occur with certain cancers. Mild hypercalcemia of malignancy (HCM) can be managed on an outpatient basis, but symptomatic moderate or severe HCM may require hospitalization. Possible symptoms include but are not limited to altered mental status, fatigue, constipation, and renal impairment. Treatment options include IV hydration, loop diuretic, calcitonin receptor agonist, bisphosphonate, receptor activator of nuclear factor kappa-B ligand inhibitor, steroid, or calcimimetic use. Of the therapies used to treat HCM, the steroid class can exacerbate underlying psychiatric conditions. Pharmacists can help develop treatment plans for their institution and can assist in determining the optimal drug, dosage, route, frequency, and therapy duration for individual patients.

Calcium is an electrolyte that is involved in several metabolic processes related to the kidneys, bones, and gastrointestinal tract as well as signaling pathways in the cardiovascular and nervous systems.¹ A normal laboratory range for blood serum calcium is 8.5 mg/dL to 10.4 mg/dL, with some variations among assays.¹ If a patient has low serum albumin, the corrected calcium level may be calculated as follows: corrected calcium = patient’s serum calcium + 0.8 * (normal albumin – patient’s serum albumin), where normal albumin is usually 4 g/dL.² However, there are limitations to this formula’s accuracy in patients with chronic kidney disease (CKD) or critical illness.² As an alternative, an ionized calcium measurement may be used.³

Hypercalcemia, which is a disorder characterized by an elevation in serum calcium levels, can cause unique symptoms and end-organ problems based on its severity.^1,2 Hypercalcemia of malignancy (HCM) is a metabolic complication of certain cancers.² As per current Endocrine Society guidelines, mild hypercalcemia is a calcium level of 10.5 mg/dL to 11.9 mg/dL, moderate hypercalcemia is 12 mg/dL to 14 mg/dL, and severe hypercalcemia exceeds 14 mg/dL.¹ Within the context of clinical trials for cancer, the Common Terminology Criteria for Adverse Events classification of hypercalcemia differs somewhat, with grade 1 being 10.5 mg/dL to 11.5 mg/dL; grade 2 being 11.6 mg/dL to 12.5 mg/dL, or symptomatic; grade 3 being 12.6 to mg/dL 13.5 mg/dL, or hospitalization indicated; and grade 4 being 13.6 mg/dL or higher, or having life-threatening consequences.⁴

Assessment

Laboratory values used to assess hypercalcemia include but are not limited to serum calcium, serum albumin, ionized calcium, parathyroid hormone (PTH), PTH-related protein (PTHrP), 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and phosphorus.^5,6 Consultations with specialty services (e.g., oncology, nephrology, endocrinology) may be warranted for additional workup and interpretation.

Whereas mild HCM may be asymptomatic and managed in the outpatient setting, symptomatic moderate-to-severe HCM is considered an oncologic emergency that may necessitate inpatient admission.⁷ Symptomatic patients may initially present with renal impairment, constipation, or fatigue.^1,2 Some other possible signs and symptoms of moderate-to-severe hypercalcemia are presented in TABLE 1.^1,2,8

Etiologies

There are a few nonmalignant etiologies of hypercalcemia (e.g., hyperparathyroidism, certain drugs).¹ As part of the multiprofessional team providing outpatient or inpatient care, pharmacists can assist during the medication-reconciliation phase by identifying potential drug-related causes. These drugs include but are not limited to calcium supplements (e.g., acetate, carbonate, citrate salts), vitamin D analogues (e.g., cholecalciferol, ergocalciferol, calcitriol), thiazide-like diuretics (e.g., chlorthalidone, hydrochlorothiazide, metolazone), and lithium.^9-13 Temporary cessation of such drugs may be indicated during hypercalcemia.

HCM may be due to processes that are humoral (mediated by 1,25-dihydroxyvitamin D, PTH, PTHrP) or local osteolytic (mediated by tumor necrosis factor, interleukin [IL]-1, or IL-6).^5,6 Humoral HCM can occur with solid tumors (e.g., breast, head/neck, lung, parathyroid, urothelium) or lymphomas, whereas osteolytic HCM can occur with solid tumors (e.g., breast, lung) or multiple myeloma (MM).⁶ Either etiology involves enhanced downstream osteoclast activity and subsequent bone resorption leading to elevated serum levels of calcium.⁶

Treatment Goals and Options

The main goals of HCM treatment are to improve the signs (e.g., serum calcium and creatinine) and symptoms of hypercalcemia and to establish an underlying etiology.⁶ Afterward, the oncology team may potentially initiate malignancy-directed therapy.⁶

The Endocrine Society has published clinical practice guidelines on the treatment of HCM in adults.² Additionally, numerous specialty reviews are available in the literature, including internal medicine, oncology, and nephrology perspectives.^5,6,14-21 The Endocrine Society recommendations call for initially restoring depleted intravascular volume with IV fluid, with or without an adjunctive loop diuretic, and reducing bone resorption with a bisphosphonate or receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitor.² For symptomatic moderate or severe HCM, calcitonin may also be used, albeit for a short period (generally, 48-72 hours). For underlying etiologies that may be steroid-sensitive (e.g., MM, lymphoma), a course of corticosteroids may be initiated.²

Drug-Specific Considerations

See TABLE 2 for a brief summary of selected drugs used to treat hypercalcemia in adults.^2,9-12

IV Fluid: Sodium chloride 0.9% (normal saline [NS]) is often recommended to restore depleted intravascular volume and enhance urinary calcium excretion.² NS has an immediate onset of action, and the duration of effect corresponds with the infusion time.² A key concern with its use is volume overload, which can be worrisome in patients who have heart failure (HF), limited urinary output, pulmonary edema, or peripheral edema.^2,9,10 Particularly with long-term inpatient administration of NS, the acid-base balance must also be considered to mitigate the risk of hyperchloremic metabolic acidosis (due to the chloride content of NS).^9,10 If this develops, ongoing hydration requirements and/or utilization of alternative IV fluids (e.g., Plasma-Lyte A, Isolyte S) should be reevaluated. Plasma-Lyte R solution and Lactated Ringer’s solution contain calcium and theoretically can increase serum calcium, but real-world data on safety and efficacy outcomes of these alternative IV fluids in hypercalcemia are needed.^9,10

Loop Diuretics: After volume repletion with IV fluids, furosemide (Lasix), bumetanide (Bumex), or torsemide (Demadex) may be administered.^2,9,10 The onset of action of these agents is within 1 hour, and the duration of effect is at least 2 hours.^2,9,10 These drugs can increase urinary calcium excretion by inhibiting resorption in the thick ascending loop of Henle via interference with the sodium-potassium-chloride cotransport system.^2,12 Loop diuretics may be preferred in patients with HF or other volume-overload states.² However, particularly in patients whose intravascular volume is not replete, the use of loop diuretics can lead to further volume depletion and worsening of hypercalcemia (e.g., acute kidney injury [AKI]).² Drugs in this class can also acutely reduce serum levels of magnesium and potassium; therefore, these electrolytes require appropriate repletion.^9,10

Calcitonin Receptor Agonist: Similar to the endogenous hormone in humans, calcitonin salmon (Miacalcin) opposes the actions of PTH by inhibiting bone resorption via interference of osteoclast function and promoting urinary calcium excretion.^2,9,10 This synthetic protein is based on the amino acid sequence of calcitonin found in salmon.⁹ The injectable (subcutaneous or intramuscular) formulation is used for hypercalcemia, whereas the intranasal formulation is reserved for osteoporosis.^9,10 It has an onset of action of approximately 6 hours, with a 6-hour to 8-hour duration of effect after each dose.^2,9,10 Unfortunately, tachyphylaxis can occur after 48 hours, as osteoclasts can undergo retraction to escape the sustained effects of calcitonin.^2,22 Considering this loss of efficacy within a short period, several institutions have placed inpatient limits on dose and duration to mitigate inadvertent and unnecessary use of injectable calcitonin beyond 48 to 72 hours.^23,24 Calcitonin can also promote urinary excretion of magnesium, phosphate, potassium, and sodium; therefore, appropriate repletion of these electrolytes is necessary.^2,9,10

Bisphosphonates: Pamidronate (Aredia), zoledronic acid (Zometa), and ibandronate (Boniva) are nitrogen-containing bisphosphonates that inhibit osteoclast-mediated bone resorption via inhibition of farnesyl pyrophosphate synthase.^2,9,10 These IV drugs have an onset of action of approximately 3 days and a duration of effect of several weeks, with zoledronic acid having a longer effect than pamidronate. Oral bisphosphonates are not indicated in HCM because of their lower potency and slower onset of action. Within the first month of HCM treatment, pamidronate or zoledronic acid may be administered every 7 days until the desired improvement in serum calcium levels is achieved.^2,9,10 Although the safety and utility of IV ibandronate for HCM have been reported, the drug is FDA approved only for osteoporosis.^25-27

Bisphosphonates can increase the risk of AKI, and strategies to mitigate this include reducing the dosage, increasing the infusion time, and increasing concurrent hydration.^2,9,10 Other acute adverse effects include transient flu-like symptoms (e.g., fever, generalized pain) and electrolyte derangements (e.g., hypocalcemia, hypophosphatemia) that require appropriate repletion.^9,10 Longer-term use of bisphosphonates can increase the risk of osteonecrosis of the jaw (ONJ) and atypical femur fracture (AFF).^2,9,10

RANKL Inhibitor: Denosumab (Prolia 60 mg, Xgeva 120 mg) is an antibody that targets RANKL and inhibits bone resorption by preventing osteoclast formation.^2,9,10 It is administered subcutaneously, with an approximate onset of action of at least 3 days and a duration of effect of several weeks. Although denosumab is indicated for treatment of HCM that is refractory to bisphosphonate therapy, recommendation 2 from the Endocrine Society guidelines specifies a preference for using denosumab over bisphosphonates. Denosumab may be administered more frequently in the first month of HCM treatment (i.e., weekly for three doses, then transitioned to monthly until desired improvement in serum calcium level).^2,9,10 The FDA approved biosimilars in March 2024 (denosumab-bbdz [Jubbonti 60 mg, Wyost 120 mg]), February 2025 (denosumab-dssb [Ospomyv 60 mg, Xbryk 120 mg]), and March 2025 (denosumab-bmwo [Stoboclo 60 mg, Osenvelt 120 mg] and denosumab-bnht [Conexxence 60 mg, Bomyntra 120 mg]); however, their market availability and cost are unclear.¹¹

Similar to bisphosphonates, RANKL inhibitors can cause acute electrolyte derangements (e.g., hypocalcemia, hypophosphatemia) and increase ONJ and AFF risk with longer-term use.^2,9,10 The 60-mg denosumab products that are approved for osteoporosis carry a boxed warning about severe hypocalcemia in patients with CKD, as this population is at greater risk for this electrolyte derangement that can lead to hospitalization and life-threatening events.^9,10 Although the 120-mg products do not have this boxed warning, similar considerations of lower doses, closer monitoring, and adequate repletion of calcium and vitamin D would be necessary, particularly in patients with HCM and concurrent renal dysfunction.^2,9,10

Steroids: Hydrocortisone (Cortef), prednisone (Deltasone), methylprednisolone (Medrol), and dexamethasone (Decadron) are steroids that can decrease intestinal calcium absorption and inhibit 1-alpha-hydroxylase (to limit 1,25-dihydroxyvitamin D production in lymphomas or granulomatous diseases).^2,9,10 Steroids also induce apoptosis of MM cells.²⁸ The dosage, route, and duration of therapy vary based on the underlying etiology of HCM.² The onset of action for reducing serum calcium levels is approximately 2 days, with the duration of effect corresponding to steroid duration.² Acute adverse effects of steroids include hypertension, fluid retention, hyperglycemia, increased appetite, gastritis, mood or mental-status changes (e.g., anxiety, restlessness), and insomnia.^9,10

Calcimimetic: Cinacalcet, an oral drug, increases the sensitivity of the calcium-sensing receptor on the parathyroid gland to reduce PTH secretion, thereby decreasing bone resorption and renal calcium reabsorption.^2,9,10 This agent may be used to treat HCM related to a parathyroid carcinoma. Adverse effects occurring in more than 10% of patients include hypotension, abdominal pain, diarrhea, nausea, vomiting, headache, back pain, muscle spasm, myalgia, cough, and dyspnea.^2,9,10

Hypocalcemia Mitigation

Particularly with bisphosphonates and RANKL inhibitors, which have a longer duration of effect, there is a risk of overcorrection of hypercalcemia, which leads to hypocalcemia.^2,9,10 In addition to baseline renal dysfunction (e.g., CKD), other risk factors include but are not limited to hematologic malignancy, bone metastases, inpatient status, and deficient baseline vitamin D levels.²⁹ Calcium and vitamin D can be supplemented, with the strategies differing by patient scenario and institutional practices.^2,30

For urgent correction of serum calcium levels, IV calcium gluconate may be administered.^9,10,30 Otherwise, oral supplementation with calcium carbonate or citrate may be initiated, with the latter preferred in patients on concurrent acid-suppressing medications (e.g., proton pump inhibitors, histamine-2 receptor antagonists).^9,10,30 Because calcium can bind phosphorus, serum phosphorus levels should be checked and supplemented accordingly.^9,10

Vitamin D may be supplemented in daily or weekly doses.^9,10,30 In patients with CKD or renal replacement therapy (e.g., hemodialysis), conversion of nutritional vitamin D to the more active form is decreased; therefore, concurrent calcitriol supplementation may be necessary.^9,10,31

Relevance to Mental Health

As indicated in TABLE 1, patients with symptomatic moderate-to-severe HCM may present with nervous system–related changes, such as fatigue, lethargy, weakness, altered mental status, cognitive dysfunction, confusion, anxiety, depression, stupor, and coma.^1,2,8 Patients with MM and high levels of heavy chains (e.g., immunoglobulin A) can develop hyperviscosity syndrome, which can contribute to altered mental status.³² Of the therapies that are used for the treatment of HCM, the steroid drug class can exacerbate underlying psychiatric conditions.^9,10

Hypothetical Scenarios

Case 1: JR is a 63-year-old female with newly diagnosed MM who comes to the clinic to discuss treatment options. Her medical history includes generalized anxiety disorder (managed with sertraline) and hypertension (treated with hydrochlorothiazide). JR reports a recent increase in thirst, constipation, and nausea. Additionally, she says that after reading about MM online, she started taking vitamin D and calcium supplements (unsure of the dose, when asked) three times daily to strengthen her bones. JR’s weight is 138 lb, and her serum creatinine is 1.3 mg/dL (baseline 0.8 mg/dL), calcium is 10.9 mg/dL, and albumin is 3.1 g/dL. The team decides to hydrate JR with 1 L of IV NS in the infusion center, administer a dose of dexamethasone 40 mg to address the hypercalcemia, and begin MM treatment. JR becomes irate and anxious in the infusion center and attempts to leave while the IV fluids are still infusing, necessitating the attendance of several team members. She is administered a dose of lorazepam 0.5 mg IV, which calms her sufficiently for hydration to be completed. She leaves the clinic in stable condition, with a plan to recheck her laboratory results the next day.

Discussion: JR was experiencing a case of mild hypercalcemia, with a corrected calcium of 11.6 mg/dL and mild clinical manifestations. Therefore, a more conservative approach with IV hydration would be appropriate. It is important to compile a complete medication list, when possible, to evaluate for potential iatrogenic causes of hypercalcemia. JR’s hydrochlorothiazide, vitamin D, and calcium may have been contributing factors, and it may have been advisable to hold these agents during this hypercalcemic event. It is also essential to consider the patient’s medical history when making treatment decisions. Because dexamethasone can cause excitatory psychiatric reactions, especially in patients receiving relatively high doses or with a history of psychiatric disorders, a lower starting dose or an alternative agent might have been necessary for JR.

Case 2: DT, a 78-year-old male, presents to the emergency department (ED) with complaints of abdominal pain, weakness, confusion, and agitation. DT’s medical history includes HF with reduced ejection fraction (HFrEF) and refractory MM. He weighs 176 lb, and his serum creatinine is 3.7 mg/dL (baseline 1.1 mg/dL), calcium is 13.5 mg/dL, and albumin is 2.3 g/dL. DT is admitted to the hospital, and the ED team starts IV hydration with a bolus of 1 L of NS and one dose of zoledronic acid 4 mg IV. DT develops shortness of breath later that day, and a chest x-ray confirms pulmonary edema. Additionally, his serum creatinine and calcium continue to increase to 5.1 mg/dL and 14 mg/dL, respectively. After consulting the nephrology specialists, the ED team schedules DT for emergent hemodialysis (HD). DT’s breathing improves, and his serum creatinine and calcium trend down to baseline over the next few days. After eventual initiation of inpatient chemotherapy for the underlying etiology, DT is discharged home with a serum creatinine of 1.4 mg/dL and planned outpatient follow-up.

Discussion: Hypercalcemia is a common initial presentation of MM. Although hydration is a typical first-line treatment approach, it should be used cautiously in patients with HFrEF, who may be unable to tolerate the additional fluid. In this case, the use of a loop diuretic (i.e., furosemide) might have been used in combination with hydration to prevent fluid overload. Bisphosphonates are also indicated in patients with moderate-to-severe hypercalcemia; however, they can cause or worsen kidney injury, particularly when given at higher doses or as short-duration infusions. Because DT presented with AKI at baseline, a lower dose of zoledronic acid or denosumab could have been considered. DT had acute indications for HD initiation (refractory electrolyte elevation, volume overload), but he did not need to continue HD upon discharge.

The Pharmacist’s Role

Several treatment options for managing HCM in adults are available, with varying mechanisms of action, onset of action, duration of effect, and adverse effects. Selection of the drug and dose is individualized based on patient-specific factors, including but not limited to hypercalcemia severity and organ function (e.g., renal, cardiac, pulmonary). Whether they are in the outpatient clinic or inpatient setting, pharmacists can provide drug information, perform ongoing due diligence when reviewing orders (e.g., clarify calcitonin exceeding a 2-day duration, or pamidronate or zoledronic acid ordered less than 7 days from prior dose), and assist with additional supportive care (e.g., calcium and vitamin D supplementation).

Considering the eventual market availability of several denosumab biosimilars, pharmacists can participate on committees to determine pathways for preferred drug selection at their institution. Additionally, pharmacists can help create institutional order panels or sets to move toward standardization of the management of hypercalcemia based on severity. Together with other members of the healthcare team, pharmacists can continue to inform the literature regarding their institutional experiences and best practices for hypercalcemia.

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