What is the comparative safety of IV bisphosphonates for the treatment of hypercalcemia in patients with renal dysfunction?

Introduction
In 2019, the University of Illinois at Chicago Drug Information Group reviewed the literature on what criteria exist to suggest the use of denosumab for the treatment of hypercalcemia of malignancy (HCM) over other calcium-reducing options, which can be accessed here.1 Given that there are still indications for intravenous (IV) bisphosphonates for hypercalcemia of any etiology, including renal dysfunction, this review summarizes the safety literature of IV bisphosphonates in patients with renal dysfunction.

Hypercalcemia is defined by corrected serum calcium levels that are two standard deviations above the normal range of calcium.2,3 Normal adult total serum calcium concentrations range from 8.5 to 10.5 mg/dL (2.12-2.62 mmol/L).2 In adults, mild hypercalcemia is 10.5 to 12 mg/dL (<3 mmol/L), moderate hypercalcemia is 12 to 13.9 mg/dL (3-3.5 mmol/L), and severe hypercalcemia is total serum calcium ≥14 mg/dL (≥3.5 mmol/L).2-4 Total serum concentration comprises free or ionized calcium (45%), calcium bound to plasma proteins (45%), and calcium bound to anions (10%).3 Ionized calcium is the physiologically active form.5 Patients may have fluctuations in plasma protein levels, such as low albumin, that may affect total body calcium but not ionized calcium.2,5 These patients should have the measured total serum calcium concentration corrected or, ideally, have ionic calcium measured instead; however, ionic calcium measurement tests are not widely available.4,5 Should a clinician need a corrected calcium level, the equation is as follows: Corrected calcium (mg/dL) = calcium measured + 0.8×[4-albumin (g/dL)].4

There are many etiologies of hypercalcemia, with primary hyperparathyroidism (pHPT) and malignancy accounting for approximately 90% of all cases.2,3 Additional causes may include granulomatous disease, vitamin D intoxication, thyrotoxicosis, drugs such as thiazides, lithium, and parathyroid hormone, immobilization, acute renal failure, chronic renal failure treated with calcium and calcitriol or vitamin D analogs, and renal transplant.2

Treatment of hypercalcemia is dependent on its severity or etiology.2,3 Measurement of serum parathyroid hormone (PTH) level is a helpful test to differentiate if the hypercalcemia is PTH related or not.2 Guidelines by the American Association of Endocrine Surgeons for Definitive Management of Primary Hyperparathyroidism state parathyroidectomy is indicated for all patients with symptomatic pHPT and when the serum calcium level is greater than 1 mg/dL above normal, regardless of symptoms.6 Medical management, followed by parathyroidectomy, is recommended for patients who present with hypercalcemic crisis (severe hypercalcemia and signs or symptoms of multiorgan dysfunction).6 Medical management of severe hypercalcemia includes hydration with saline and treatment with IV bisphosphonates with or without calcitonin.2 The Endocrine Society guidelines for the treatment of HCM in adults recommend treatment with denosumab or an IV bisphosphonate.7 For severe HCM, a combination of calcitonin and an IV bisphosphonate or denosumab is suggested. For other etiologies of severe hypercalcemia, recommended treatment includes saline and IV bisphosphonates with or without calcitonin, followed by treatment specific to the condition.2,3

An important consideration for treating any hypercalcemia is the presence of underlying renal dysfunction. The Endocrine Society notes that IV bisphosphonates may worsen renal function, in which denosumab would be preferred.7 However, there still may be situations, such as lack of accessibility or contraindications to denosumab, where alternative therapies are needed. In the case of treatment with an IV bisphosphonate in patients with renal insufficiency (creatinine clearance [CrCl] < 60 mL/min), the off-label renal dosing of zoledronic acid is for its administration over 30 to 60 minutes; for pamidronate, the administration is over 2 to 24 hours.7

IV bisphosphonates in hypercalcemia and renal dysfunction
In HCM, osteoclastic hyperactivity results in excessive bone resorption. IV bisphosphonates work principally through inhibition of bone resorption.8,9 The IV bisphosphonates currently available in the United States (US) include ibandronate, pamidronate, and zoledronic acid (Table 1). Pamidronate and zoledronic acid are approved by the US Food and Drug Administration (FDA) for the indication of HCM. Ibandronate has published evidence of use for HCM but does not currently have this FDA-approved indication.10,11 None of the IV bisphosphonates available in the US have FDA-approved indications for other types of hypercalcemia.8-10

Table 1. IV bisphosphonates8-11
Generic NameDosing in HCMRenal Considerations
Ibandronate2 or 4 mgaDo not administer to patients with severe renal impairment (CrCl <30 ml/min)
PamidronateModerate hypercalcemia (corrected serum calcium 12 to 13.5 mg/dL):
60 to 90 mg as a single dose over 2 to 24 hours

Severe hypercalcemia
(corrected serum calcium >13.5 mg/dL): 90 mg as a single dose over 2 to 24 hours		Longer infusions (ie, >2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency

Limited pharmacokinetic data exist in patients with CrCl <30 mL/min. For the treatment of HCM, clinical judgment should determine whether the potential benefit outweighs the potential risk in such patients
Zoledronic acid4 mg as a single-use IV infusion over no less than 15 minutesAdverse reactions may be greater in patients with impaired renal function. Patients with SCr > 4.5 mg/dL were excluded from clinical studies. For HCM in patients with severe renal impairment, treatment should be considered only after evaluating the risks and benefits of treatment.
aOff-label dose
Abbreviations: CrCl=creatinine clearance; HCM=hypercalcemia of malignancy; IV=intravenous; SCr=serum creatinine.

Literature review
No randomized controlled trials were identified investigating the use of IV bisphosphonates in patients with renal dysfunction (ie, CrCl < 60 mL/min). Two comparative retrospective chart reviews explicitly investigate IV bisphosphonate safety: one specific to pamidronate and another comparing pamidronate with zoledronic acid.12,13 Four case series describe the use of pamidronate (N=3) or ibandronate (N=1) in patients with renal dysfunction and hypercalcemia of varying causes.14-17 In a similar population, four case reports were identified describing the use of pamidronate (N=3) or zoledronic acid (N=1).18-21 Additional information on each of these studies are summarized in Table 2.

Table 2. Literature evaluating IV bisphosphonates for hypercalcemia of any etiology in renal dysfunction12-21
Study design and durationSubjectsInterventionsResultsConclusions
Retrospective chart reviews
Norman 202112

Retrospective chart review

Patients followed for 7 days		N=141 adult patients with HCM (25 with existing renal dysfunction; 116 with normal renal function)

Baseline CrCl in pre-existing renal dysfunction group=22.5 mL/min (IQR, 8.8)

Baseline CrCl in normal renal function=59.8 mL/min (IQR, 42.4)		Pamidronate 30 mg, 60 mg, or 90 mg IV as a one-time dosePrimary outcome of AKI occurred in 2 (8%) of patients with pre-existing renal dysfunction compared with 4 (3.4%) of patients without pre-existing renal dysfunction
No significant differences found in AKI incidence based on pamidronate dose (30 mg, 60 mg, or 90 mg) in patients with pre-existing renal dysfunction		Use of pamidronate for HCM may be useful in the setting of renal dysfunction
Palmer 202113

Retrospective chart review

Data collected up to 30 days after treatment		N=113 adult patients with hypercalcemia secondary to all causes and CrCl < 60 mL/min

Primary diagnosis of HCM in 83% of patients

Baseline median CrCl was 34.9 mL/min		Pamidronate IV at doses of 15-30 mg, 60 mg, or 90 mg (N=55)

Zoledronic acid IV at doses of 3-3.5 mg or 4 mg as a single dose (N=58)		Primary outcome of all-grade SCr elevations occurred in 27.3% of patients in pamidronate group and 24.1% in zoledronic acid group (p=0.8299).

Secondary endpoint of all-grade hypocalcemia by day 30 occurred in 38.1% of patients who received pamidronate and 25.8% of patients who received zoledronic acid		Findings show potential benefit of IV bisphosphonate use in patients with renal dysfunction; however, caution should still be utilized
Case series
Henrich 200614

Case series		N=7 adult patients with multiple myeloma, acute renal failure (CrCl 9-37 mL/min), and hypercalcemia (2.59-3.63 mmol/L)Ibandronate 2 mg, 4 mg, or 6 mg IV infused over 30 minutes as a single dose; two patients received second dose of 4 mg or 6 mgAll patients had reduced serum calcium level reductions to normal range

No cases of acute tubular necrosis or collapsing glomerulonephritis occurred and renal tolerability was maintained		IV ibandronate is associated with renal function and calcium level improvements in patients with hypercalcemia and multiple myeloma
Torregrosa 200315

Case series		N=13 adult patients on HD with secondary HPT, hypercalcemia, and osteopeniaPamidronate 60 mg as IV infusion every 2 months during HD sessions

Additional medications included IV calcitriol and phosphate binders		All patients had improvement in BMD

No adverse events occurred during or after pamidronate infusions		IV pamidronate was effective in patients on HD with severe secondary HPT
Machado 199616

Case series		N=31 adult patients with hypercalcemia in cancer and renal insufficiency (defined as SCr ≥ 1.5 mg/dL)

Average baseline SCr=2.7 ± 1.5 mg/dL		Pamidronate 60 mg or 90 mg as a single dose mixed in normal saline given as slow infusion over 24 hours; two patients received second dose of 30 mg or 45 mgSerum calcium normalized in 26 patients (84%)

One patient did not respond to treatment

Asymptomatic hypocalcemia (serum calcium < 8.5 mg/dL) occurred in 13 cases

One patient had hypocalcemia with nadir serum calcium of 4.8 mg/dL

Worsening of renal function occurred in 8 cases, reported to be unrelated to pamidronate administration		Pamidronate appeared to be a safe drug in patients with renal impairment when given with adequate hydration over 24 hours
Davenport 199317

Case series		N=10 adult patients with ESRD on CAPD or HD and hypercalcemia due to use of calcium-based phosphate binders and alfacalcidol

Mean baseline serum calcium=3.89 mmol/L (range, 3.44-4.74)		Pamidronate 30 mg or 60 mg (based on baseline corrected serum calcium and body weight) IV as a single doseSerum calcium levels decreased to 2.92 mmol/L (range, 2.79-3.84) by day 3 after pamidronate administration (p < 0.01)

No adverse effects occurred following administration of pamidronate		Pamidronate was an effective agent in reducing serum calcium in patients on HD with hypercalcemia
Case reports
Kulkarni 202318

Case report		One 50-year-old male with hypercalcemia due to TB lymphadenitis and SCr=3.92 mg/dLZoledronic acid, dose unspecified

Additional medications include calcitonin		Patient’s serum calcium levels and renal parameters showed improved after 4 days of admission

Authors did not report on adverse events		Case demonstrated use of zoledronic acid and calcitonin in patient with hypercalcemia and renal dysfunction
Mahmoud 201819

Case report		One 61-year-old female with ESRD on HD with HCMPamidronate 60 mg IV as a single dose followed by second 60 mg IV dose eight weeks laterPatient’s serum calcium decreased from 3.1 to 2.5 mmol/L over 4 days after first administration and then from 2.87 to 2.46 mmol/L over 2 days after second administration

No adverse events were identified per authors		Case demonstrated use of pamidronate 60 mg IV in a patient with ESRD on HD without noticeable adverse events
Boumans 201320

Case report		One 50-year-old female with hypoparathyroidism secondary to Riedel’s thyroiditis with severe hypercalcemia due to vitamin D intoxication and acute renal failurePamidronate 60 mg IV as a single dose

Patient was also treated with dihydrotachysterol, a vitamin D analogue with long half-life		Patient’s serum calcium decreased from 6.16 to 2.07 mmol/L over 8-day admission

Patient presented with hypocalcemia (serum calcium=1.53 mmol/L) on day 13, leading to readmission		Case demonstrated adverse event possible in patients with hypercalcemia due to vitamin D intoxication when treated with pamidronate 60 mg IV.
Czosnowski 200921

Case report		One 68-year-old male with hypercalcemia due to tertiary HPT and ESRD on HDPamidronate 30 mg IV infusion over 4 hours

Additional medications included sevelamer 800 mg three times daily and cinacalcet 60 mg once daily		Patient’s corrected serum calcium improved from baseline of 11.9 mg/dL to 10.6 mg/dL at Day 5 after pamidronate administration. Corrected serum calcium was 10.5 mg/dL 6 months post pamidronate administration

Authors did not report on adverse events		Pamidronate administration in a case of HPT and ESRD on HD resulted in sustained decrease in serum calcium concentration
Abbreviations: AKI=acute kidney injury; BMD=bone mineral density; CAPD=continuous ambulatory peritoneal dialysis; CrCl=creatinine clearance; ESRD=end-stage renal disease; HCM=hypercalcemia of malignancy; HD=hemodialysis; HPT=hyperparathyroidism; IQR=interquartile range; IV=intravenous; SCr=serum creatinine; TB=tuberculosis.

Conclusion
Despite the lack of controlled clinical trials evaluating IV bisphosphonates in hypercalcemia and renal dysfunction, available literature suggests the potential use of pamidronate, zoledronic acid, or ibandronate.12-21 Pamidronate has the most published literature identified and ibandronate has the least. Patient populations varied, with different cut-offs of either baseline CrCl or serum creatinine (SCr), and variability of patients explicitly on hemodialysis. The comparative retrospective analysis of pamidronate versus zoledronic acid did not find any significant differences in the safety outcomes of SCr increase nor hypocalcemia.13 Of the data reported from case series and case reports identified, there were 15 cases of hypocalcemia associated with use of pamidronate.16,20 Pamidronate was first approved by the FDA in 1991, specifically for the indication of HCM; zoledronic acid was approved in 2001 for the same indication.22 Ibandronate lacks this indication. All IV bisphosphonates have labeled warnings about the risk of deterioration in renal function and hypocalcemia.8-10 Manufacturers of pamidronate and zoledronic acid state to assess benefits versus risks of treatment but do not have specific renal dosing for patients with HCM and severe renal dysfunction.8,9 Based on the available information, no one IV bisphosphonate is definitively safer than the other for use in hypercalcemia in renal dysfunction. Future investigations are needed to better understand the best therapy in this patient population.

References

  1. What criteria exist to suggest use of denosumab for the treatment of hypercalcemia of malignancy over other calcium reducing options? UIC Drug Information Group website. Published November 2019. Accessed August 26, 2024. https://dig.pharmacy.uic.edu/faqs/2019-2/november-2019-faqs/what-criteria-exist-to-suggest-use-of-denosumab-for-the-treatment-of-hypercalcemia-of-malignancy-over-other-calcium-reducing-options/
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  7. El-Hajj Fuleihan G, Clines GA, Hu MI, et al. Treatment of hypercalcemia of malignancy in adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2023;108(3):507-528. doi:10.1210/clinem/dgac621
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Prepared by:
Jacqueline Wasynczuk, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

September 2024

The information presented is current as of August 23, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.