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Malignancy-Associated Hypercalcemia: Which Bisphosphonate is Best?

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]
2.
Grill V, Martin T. Hypercalcemia of malignancy. Rev Endocr Metab Disord. 2000;1(4):253-263. [PubMed]
3.
Flombaum C. Metabolic emergencies in the cancer patient. Semin Oncol. 2000;27(3):322-334. [PubMed]
4.
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]
5.
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.
7.
Bounameaux H, Schifferli J, Montani J, Jung A, Chatelanat F. Renal failure associated with intravenous diphosphonates. Lancet. 1983;1(8322):471. [PubMed]
8.
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]
9.
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]
10.
Product Information: AREDIA(R) IV injection, pamidronate disodium IV injection. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2008.
11.
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]
14.
Cheer S, Noble S. Zoledronic acid. Drugs. 2001;61(6):799-805; discussion 806. [PubMed]
15.
Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998;19(1):80-100. [PubMed]

ALiEM Copyedit

Hi Meghan,

Thank you for your interesting contribution. I have to admit, this was certainly an area that I had to read up on.

My biggest question is the necessity of initiating biphosponate therapy in the ED. This is certainly a rarely used class of medications in the ED, and I think many practitioners would be hesitant to \"pull-the-trigger\" without discussion with heme-onc or possibly endocrine. Can you clarify any relative or absolute contraindication? Have you encountered any EM literature or other literature emphasizing the importance of urgent/emergent administration?

Additionally, what degrees of hypercalcemia do you recommend initiation on biphosphonate therapy? Should mild or asymptomatic hypercalcemia in the content of malignancy by considered?

Finally, what other factors should be considered before initiation on therapy? How should renal function, albumin, phos and other electrolytes be taken into consideration?

Overall, certainly an intriguing topic, well-written, and good flow to the article. I would love to have a little more information to help EM physicians feel comfortable that they are making a well-educated and appropriate choice for their patients.

Let me know if you have any questions or need any assistance.

Thanks,
Sam Shaikh

Sameed Shaikh, MD
ALiEM-CORD Fellow, Emergency Medicine Resident, Wayne State School of Medicine. Founder: SamsStudyGuides.com

Dr. Shaikh,
Thank you for your thoughtful comments. I\'ve tried to update the post to more clearly answer your questions.

  1. I understand some potential hesitation about starting bisphosphonate therapy in the ED due to unfamiliarity. However, because these agents have a delayed onset of effect, earlier administration is likely to have a beneficial effect on resolution of symptoms (although I\'m not aware of any outcomes data on this). It is important to note that these measures to treat hypercalcemia don\'t change mortality for these patients if the underlying malignancy isn\'t treated appropriately.
  2. There aren\'t formal guidelines that I\'ve come across that delineate criteria for initiating therapy in the ED. However, the expert opinion that I have encountered suggests that therapy beyond IV fluids should be started in the presence of neurologic or cardiac symptoms (which may indicate a rapid rise in serum calcium) or severe hypercalcemia (greater than 14 mg/dL) warrant prompt treatment. Mild or moderate patients can likely wait for that admission to the oncology service to manage them accordingly.
  3. I\'ve outlined the contraindications to pamidronate and zoledronic acid in the post, including a mention of avoiding zoledronic acid in patients with severe renal impairment. I have elected at this point not to go into further detail regarding albumin (more for correction of the calcium level) and phosphorous (for monitoring purposes and other supportive measures) in order to keep the post succinct and focused on the main points of comparing/contrasting bisphosphonate therapy.

Overall, I think your comments have definitely helped to make the post clearer and more informative for the reader!

Thanks again for your perspective,
Meghan

Meghan Groth, PharmD, BCPS
Emergency Medicine Pharmacy Clinician, Fletcher Allen Health Care; Contributor for the Emergency Medicine PharmD Blog

Expert Peer Review

Hi Meghan,

I first want to echo the point made by Sameed, in that most ED prescribers are going to wait until other consultants are on the case before initiating bisphosphonates in the ED. Particularly since there are several therapies that should be started prior (fluid, loop diuretic, steroid, +/-calcitonin), and other worrisome abnormalities (hyperuricemia, hyperkalemia, renal issues, immunosuppression, etc.) that can occur in this patient population. Nevertheless, it is still important for ED folks to be aware of these drugs.

Given that the decision of which drug to stock on formulary was probably made without consideration of the ED at P&T meetings, the choice of which agent to use has probably already been made. As discussed on the EMPharmD blog, there are renal dosing options for zoledronic acid for patients with GFR < 60. In this type of patient, I would put money on some degree of renal impairment, so be cautious with dosing. Similar considerations should be made with pamidronate since it hasn\'t been studied in GFR < 30.

Furthermore, these drugs can cause severe bone pain in patients, and almost everyone will get nauseous and vomit. Therefore, being prepared with pain control strategies and antiemetics would help.

Craig Cocchio, PharmD, BCPS
Clinical Assistant Professor, Emergency Medicine, Residency Program Director, Editor-in-Chief of Emergency Medicine PharmD Blog

Hi Craig,

Thanks for taking the time to review this post and provide feedback!

I wholeheartedly agree that consultation with the appropriate services (e.g. oncology) is essential to the appropriate management of these patients. However, for those ED providers that practice in institutions without 24/7 access to these specialists, I think it\'s important that ED providers feel comfortable in initiating bisphosphonate therapy if necessary. Agreed that some other interventions may take precedence (mainly IV fluids), but others (like steroids) are only warranted in hypercalcemia of specific etiologies, and it may make sense to use a therapy like calcitonin to \"bridge\" with bisphosphonates until they\'ve had a chance to take effect. From my understanding of the literature (see reference cited above), loop diuretics are not routinely recommended, and would be reserved for volume overloaded patients.

Even though ED providers may not be the primary decision makers with regard to which bisphosphonates are added to hospital formularies, many institutions have ED representation on the Pharmacy and Therapeutics Committee. My intention in writing this post was to inform the reader about the differences between the statistical significance claimed by the authors of the comparative study between pamidronate and zoledronic acid, and the clinical significance of their respective calcium-lowering effects. I had hoped that after reading, ED providers could provide an informed voice regarding the choice of bisphosphonate when caring for these patients, just as they would in discussion with other sub-specialty consult services when jointly taking care of patients in the ED (e.g. antiplatelet therapy choices in patients with acute coronary syndrome).

Finally, I\'ve updated the post to reflect more clearly the dose adjustment recommendations for pamidronate in patients with renal dysfunction.

Again, I very much appreciate the time you\'ve taken to go through this!

Meghan

Meghan Groth, PharmD, BCPS
Emergency Medicine Pharmacy Clinician, Fletcher Allen Health Care; Contributor for the Emergency Medicine PharmD Blog

Expert Peer Review

Hi Meghan,

Thank you for the post on this interesting topic. It is certainly well written and thorough. Please take some of these suggestions into consideration:

  1. I want to echo the EM-specific concerns as mentioned by Drs. Shaikh and Cocchio. I also want to add, if there are any specific hints/pearls when it comes to evaluation of patients with suspected hypercalcemia it would be great noting them here (i.e., specific EKG findings, physical exam signs that are unique to hypercalcemia – things that EM clinicians should be aware of in the first 15 minutes of meeting the patient). I know that hypercalcemia can be very non-specific, but if you have/find any pearls they would be much appreciated by ALiEM readers.
  2. It would also be great to see the comparison trials between Zoledronic Acid and Pamidronate in a little more detail. For example, consider including a PICO analysis chart, as this will be a quick reference for busy clinicians.

Patients: what type of patients were studied, what kind of tumors, in what setting;

Intervention: what drug was studied, dosing, infusion intervals, special considerations and contraindications;

Comparison: placebo vs active control, it would also be beneficial to note the source of funding, as industry sponsored trials are much more likely to show a positive result or benefit;

Outcome: lab values vs. patient specific outcomes and if these outcomes would be an immediate goal for emergency clinicians while the patient is in the emergency department.
Thank you again for your hard work in writing this up. Please do not hesitate to contact me if you have any questions.

Best,

Zlatan Coaralic

Zlatan Coralic, PharmD
Assistant Clinical Professor of Pharmacy & EM; Emergency Department Clinical Pharmacist; University of California, San Francisco

Hi Zlatan,

Thanks for taking the time to provide feedback on my post. Your comments will definitely improve the post and make it more informative.

I\'ve provided responses below:

  1. I hesitate a bit to attempt to expand on the diagnosis aspect of this disease state. I\'m rather close to the word limit as it is, and don\'t know that I could address pearls of patient assessment in a way that would do this topic justice (without making the post too long for this format).
  2. I think including a PICO chart is a great idea! I\'ve added this in with details regarding the trial comparing pamidronate with zoledronic acid.

Thanks again for your comments,
Meghan

Meghan Groth, PharmD, BCPS
Emergency Medicine Pharmacy Clinician, Fletcher Allen Health Care; Contributor for the Emergency Medicine PharmD Blog
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

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