Calcium-canstockphoto9689385 (1)Malignancy-associated hypercalcemia (MAH) is the most common metabolic derangement encountered in the oncologic population in the ED. It can occur in up to 30% of cancer patients at some point during the disease.1–3 Clinical manifestations include mental status changes (which may progress to coma) and renal impairment.3 These patients may be classified based on both type and severity. Therapies for managing MAH emergently should focus on correcting the underlying mechanism, as outlined below with their respective causes:3

  1. Osteoclastic bone resorption – osteolytic hypercalcemia, 1,25(OH)2D-secreting lymphomas, humoral hypercalcemia of malignancy, and ectopic hyperparathyroidism
  2. Renal tubular calcium reabsorption – humoral hypercalcemia of malignancy, ectopic hyperparathyroidism
  3. Intestinal absorption of calcium – ectopic hyperparathyroidism, 1,25(OH2D-secreting lymphomas

In the ED, attention should be paid to medication causes of hypercalcemia (lithium, calcitriol, vitamin D, and thiazide-type diuretics) as well as minimizing the use of sedative agents, which may make neurologic evaluation difficult. Patients with MAH are often dehydrated due to decreased oral intake and a renal water-concentrating defect directly caused by elevated calcium levels.3 Therefore, intravenous (IV) fluid resuscitation is a logical first-line therapy. Routine administration of loop diuretics, such as furosemide, has largely fallen out of favor (unless the patient is volume-overloaded) because of the concern of worsening volume depletion in this population.4

Rationale for bisphosphonate use

Patients with neurologic or cardiac symptoms, as well as those with severe hypercalcemia (which most regard as a serum calcium level greater than 14 mg/dL) warrant prompt intervention.3 Many experts recommend initiation of a bisphosphonate as soon as possible due to the delayed onset of effect (see more below).3,5 Bisphosphonate therapy has the most data behind it, and is a relatively safe and effective intervention to be initiated in the ED.3 These agents inhibit osteoclastic bone resorption, making them highly effective in addressing #1 above. Several bisphosphonates are available in the US in IV formulations (pamidronate, zoledronic acid, ibandronate, and etidronate). Of these, pamidronate, zoledronic acid, and etidronate are currently approved for MAH. Etidronate carries a higher risk of increasing serum creatinine than the other agents.6,7 So, that narrows the discussion down to the choice between zoledronic acid and pamidronate for ED management of MAH.

Comparison of zoledronic acid and pamidronate

Zoledronic acid is a third-generation bisphosphonate with potency approximately 100-times that of pamidronate.8 Both agents are currently-FDA approved for MAH. Aside from potency, several important differences between the two exist (1) infusion time (2) preparation and (3) acquisition cost. Pamidronate is only contraindicated in patients with a hypersensitivity to bisphosphonates; zoledronic acid is contraindicated in patients with a creatinine clearance less than 35 mL/minute due to the concern for precipitating acute kidney injury, although this is documented most often in patients with high or repeated doses.9 Dose reduction is recommended for pamidronate in patients severe renal impairment, but extensive study in this patient population is lacking.10

Only one study (see table below) has compared the calcium-lowering effects of zoledronic acid and pamidronate in a population of patients with MAH.11 The authors of the study boldly start the title by stating “Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy,” but that’s a bit misleading. The calcium concentrations at day four were only significantly different between the 8 mg zoledronic acid group and the pamidronate group. Zoledronic acid is only approved at a 4 mg dose in the US for MAH, and this dose did not show a difference in calcium concentrations at day 4 when compared to pamidronate. Additionally, the nadir calcium concentrations between zoledronic acid and pamidronate were 9.8 mg/dL and 10.5 mg/dL (normal range 8.5 to 10.5 mg/dL), respectively. While this may have reached statistical significance, the clinical significance is questionable. Tolerability and incidence of adverse events were similar between the two agents in this trial.

Population

Included: 287 adult patients with cancer (one-third breast and hematologic, two-thirds “other”) and severe hyprecalcemia of malignancy (corrected serum calcium (CSC) at least 12 mg/dL).

Notable Exclusions: patients treated with bisphosphonates in previous 90 days, serum creatinine > 4.5 mg/dL, “severe dehydration,” new cytotoxic chemo initiated within 7 days, or calcitonin adminstration within 72 hours.

Intervention Single dose of zoledronic acid (4 mg or 8 mg) IV over 5 minutes or single dose of pamidronate 90 mg IV over 2 hours; IV fluids also administered at time of study drug
Comparison Active control in this trial was pamidronate group; study funded by Novartis Pharma, makers of Zometa (zoledronic acid)
Outcomes Evaluated

Primary: Complete response by day 10, defined as CSC < 10.8 mg/dL.

Other: Time to relapse (serum calcium greater than 11.6 mg/dL), duration of response (CSC less than 11.6 mg/dL), duration of complete response (CSC < 10.8 mg/dL), and efficacy of re-treatment for relapsed or refractory hypercalcemia of malignancy.

Zoledronic acid has the “advantage” of an infusion time of only 15 minutes for a 4 mg dose, where pamidronate has to be infused over at least two hours.10,12 While this may seem inconvenient for ED administration, it is likely an irrelevant factor if the patient is sick enough to require hospital admission. Additionally, some may extrapolate a faster infusion time with a faster onset of action. This is not the case. These agents take at least 24-48 hours to work, with a nadir occurring between days four and seven.13–15 Taking this into account, an infusion time of 15 minutes as compared to 120 minutes again seems irrelevant. The formulation of zoledronic acid approved for use in MAH is a 100 mL ready-to-infuse solution; pamidronate must be diluted in at least 500-1000 mL of fluid for infusion.10,12 While the 100 mL preparation might be convenient for outpatient infusion settings, MAH patients often require IV fluids anyway. The preparation of pamidronate is another way to provide fluid resuscitation to these often volume-depleted patients.

One difference between the two agents that is fairly significant is cost. Zoledronic acid has an average wholesale price of approximately $1000 for a single 4 mg dose. In contrast, a 90 mg dose of pamidronate has a price tag of about $144. In the outpatient infusion setting, this may not matter as much when considering preparation, infusion time, and nursing care associated with a longer infusion. However, it is unlikely that this substantially higher cost carries the same value in the ED.

Bottom Line

  • Malignancy-associated hypercalcemia is an important cause of hypercalcemia encountered in the ED.
  • ED management should focus on IV fluid resuscitation and initiation of bisphosphonate therapy.
  • Zoledronic acid and pamidronate are the two IV agents most studied for MAH. Although zoledronic acid is more potent and can be infused more rapidly, it appears that calcium-lowering effects do not differ clinically, and thus pamidronate may be considered a reasonable and more cost-effective alternative in the ED.
1.
Stewart A. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352(4):373-379. [PubMed]
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Grill V, Martin T. Hypercalcemia of malignancy. Rev Endocr Metab Disord. 2000;1(4):253-263. [PubMed]
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Flombaum C. Metabolic emergencies in the cancer patient. Semin Oncol. 2000;27(3):322-334. [PubMed]
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LeGrand S, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Ann Intern Med. 2008;149(4):259-263. [PubMed]
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Bilezikian J. Clinical review 51: Management of hypercalcemia. J Clin Endocrinol Metab. 1993;77(6):1445-1449. [PubMed]
6.
Product Information: Didronel(R) oral tablets, etidronate disodium oral tablets. Warner Chilcott (US), LLC (per Manufacturer), Rockaway, NJ, 2011.
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Bounameaux H, Schifferli J, Montani J, Jung A, Chatelanat F. Renal failure associated with intravenous diphosphonates. Lancet. 1983;1(8322):471. [PubMed]
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Rosner M, Dalkin A. Onco-nephrology: the pathophysiology and treatment of malignancy-associated hypercalcemia. Clin J Am Soc Nephrol. 2012;7(10):1722-1729. [PubMed]
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Markowitz G, Fine P, Stack J, et al. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int. 2003;64(1):281-289. [PubMed]
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Product Information: AREDIA(R) IV injection, pamidronate disodium IV injection. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2008.
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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(2):558-567. [PubMed]
12.
Product Information: ZOMETA(R) IV injection, zoledronic acid IV injection. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2008.
13.
Nussbaum S, Younger J, Vandepol C, 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(3):297-304. [PubMed]
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Cheer S, Noble S. Zoledronic acid. Drugs. 2001;61(6):799-805; discussion 806. [PubMed]
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Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998;19(1):80-100. [PubMed]
Meghan Groth, PharmD, BCPS

Meghan Groth, PharmD, BCPS

Emergency Medicine Pharmacy Clinician
University of Vermont Medical Center
Contributor for Emergency Medicine PharmD Blog
Meghan Groth, PharmD, BCPS

@EMPharmGirl

Just a pharmacist interested in Emergency Medicine, teaching, and #FOAMed | Pharmacocontrarian | Also, like, a very stable genius
Meghan Groth, PharmD, BCPS

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