Zoledronic Acid Is Superior to Pamidronate in the Treatment of Hypercalcemia of Malignancy: A Pooled Analysis of Two Randomized, Controlled Clinical Trials

Design

Two identical, concurrent, parallel, multicenter, randomized, double-blind, double-dummy trials

N= 287

Objective

To compare the efficacy and safety of zoledronic acid and pamidronate for treating hypercalcemia of malignancy (HCM)

Study Groups

Zoledronic acid 4 mg (n= 86)

Zoledronic acid 8 mg (n= 90)

Pamidronate 90 mg (n= 99)

Re-Treatment Zolendronic Acid 8 mg (n= 69)

Inclusion Criteria

Adults with histologic or cytologic confirmation of cancer, severe HCM (defined as baseline corrected serum calcium [CSC] ≥3.00 mmol/L or 12.0 mg/dL)

Exclusion Criteria

Patients treated with bisphosphonates for hypercalcemia within 90 days or for other complications within 30 days of study entry; had a serum creatinine level > 4.5 mg/dL; had received calcitonin within 72 hours; had been treated with mithramycin, newly initiated antineoplastic cytotoxic chemotherapy or hormone therapy within 7 days, gallium nitrate within 14 days, or an investigational drug within 30 days of study entry; or had severe dehydration, were unable to tolerate IV hydration, or had hyperparathyroidism, adrenal insufficiency, or multiple endocrine neoplasia syndromes

Methods

Patients were randomized to receive either a single dose of zoledronic acid (4 or 8 mg) via a 5-minute IV infusion or pamidronate (90 mg) via a 2-hour IV infusion. One day prior to the study drug administration, patients underwent a complete physical examination, including a urinalysis and venous blood draw for serum chemistry (corrected serum calcium [CSC], parathyroid hormone-related protein [PTHrP] levels, complete blood counts with differential and platelet counts, among others). Alongside the bisphosphonate therapies, patients received IV hydration (500 mL over 4 hours), with 250 mL administered prior to the study drug infusion. The remaining IV fluids were given as part of a double-dummy infusion to maintain the double-blind nature of the trial.

Patients who were refractory to initial therapy or relapsed within 56 days after the initial treatment were re-treated with a single 8 mg dose of zoledronic acid via a 5-minute infusion. Relapse was defined as CSC ≥2.90 mmol/L (11.6 mg/dL). Re-treatment was also initiated if CSC did not decrease by ≥0.05 mmol/L (0.2 mg/dL) from baseline on day 4, by ≥0.25 mmol/L (1.0 mg/dL) on day 7, or if CSC was ≥2.90 mmol/L on day 10. Follow-up for these patients continued for an additional 28 days or until relapse, with monitoring on days 1, 4, 7, 10, 14, 21, and 28. Standard antineoplastic therapies and cytokines were permitted to be administered concomitantly throughout the study.

Duration

Intervention: Administration time was approximately 4 hours and 5 minutes

Follow-up: Up to 56 days after study drug administration or until relapse (additional follow-up)

Outcome Measures

Complete response (CR) by day 10, response duration, time to relapse

Baseline Characteristics

Zolendronic Acid 4 mg (n= 86)

Zolendronic Acid 8 mg (n= 90)

Age, years

Male

White

Baseline CSC, mmol/L

Mean

Range

3.49

3.02-4.71

3.42

3.00-4.68

3.49

3.00-5.16

3.17

2.75-4.23

Baseline PTHrP

≤2 pmol/L

>2 pmol/L

62 (72.1%)

20 (23.3%)

59 (65.6%)

25 (27.8%)

65 (65.7%)

24 (24.2%)

41 (59.4%)

20 (33.3%)

BUN/Cr ratio median

18.8

17.4

15.6

17.0

Use of loop diuretics, days 1-10

22 (25.6%)

24 (26.7%)

21 (21.2%)

11 (15.9%)

Prior use of bisphosphonates in past year

9 (10.5%)

4 (4.4%)

8 (8.1%)

6 (8.7%)

Abbreviations: CSC, corrected serum calcium; PTHrP, parathyroid hormone-related protein; BUN/Cr, blood urea nitrogen/creatinine

Results

Endpoint

Zolendronic Acid 4 mg (n= 86)

Zolendronic Acid 8 mg (n= 90)

Pamidronate 90 mg (n= 99)

CR normalization by day 10*

88.4%

86.7%

69.7%

52%

Abbreviations: CR, complete response

*p= 0.002 for zoledronic acid 4 mg; p= 0.015 for zoledronic acid 8 mg 

Mean CSC levels at days 4, 7, and 10 were significantly lower (p≤ 0.05) in patients treated with 4 or 8 mg of zoledronic acid compared to the pamidronate group. Findings were provided within a figure.

Median CR duration was 32 and 43 days for zoledronic acid (4 mg and 8 mg, respectively) vs. 18 days for pamidronate. Findings were provided within a figure.

Median time to relapse was 30 days (p= 0.001) for patients treated with 4 mg zoledronic acid and 40 days (p= 0.007) for those treated with 8 mg, compared to 17 days in the pamidronate group. Findings were provided within a figure. 

After re-treatment with 8 mg of zoledronic acid, mean CSC values decreased from 3.17 mmol/L to 2.71 mmol/L by day 10, with 52% of patients achieving CR. The median duration of CR was 10.5 days, the response lasted 15 days, and the median time to relapse was 8 days.

Adverse Events

Common Adverse Events (zoledronic acid 4 mg vs. zoledronic acid 8 mg vs pamidronate 90 mg): fever (44.2% vs. 34.7% vs. 33.0%), anemia (22.1% vs. 27.6% vs. 17.5%), nausea (29.1% vs. 21.4% vs. 27.2%), constipation (26.7% vs. 19.4% vs. 12.6%), dyspnea (22.1% vs. 18.4% vs. 19.4%)

Serious Adverse Events (zoledronic acid 4 mg vs zoledronic acid 8 mg vs pamidronate 90 mg): Grade 3 renal toxicity (2.3% vs 3.1% vs 3.0%), Grade 4 renal toxicity (0% vs 2.1% vs 1.0%), confusion and hallucination (1 patient in 4 mg zoledronic acid group), thrombocytopenia (1 patient in pamidronate group)

Percentage that Discontinued due to Adverse Events: Not disclosed

Study Author Conclusions

IV zoledronic acid provides a more effective and more convenient treatment for HCM than pamidronate, while maintaining a similar safety profile. Given that pamidronate has been the standard of care for HCM until now, it is likely that zoledronic acid will replace it as first-line therapy. Zoledronic acid is superior to pamidronate; 4 mg is the dose recommended for initial treatment of HCM and 8 mg for relapsed or refractory hypercalcemia.

InpharmD Researcher Critique

While this study demonstrated that zoledronic acid was superior to pamidronate, the follow-up duration of 56 days may potentially not be sufficient to assess long-term outcomes. Additionally, patients who relapsed or were refractory to initial treatment were re-treated with zoledronic acid, which may introduce bias when comparing the efficacy between zoledronic acid and pamidronate.

Effect of Zoledronic Acid and Pamidronate on Renal Function 

Design

Retrospective, cohort analysis

 N= 196

Objective

To determine the incidence of acute kidney injury (AKI) in patients after receiving zoledronic acid or pamidronate

Study Groups

Pamidronate group (n= 33)

Zoledronic acid group (n= 158)

Inclusion Criteria

Exclusion Criteria

Pregnant women; recent administration of a bisphosphonate within 30 days before receiving zoledronic acid or pamidronate

Methods

This study was conducted at a single academic medical center, where patients received a single dose of either intravenous zoledronic acid or pamidronate. Pearson’s chi-square or Fisher’s exact test was used to analyze categorical data, while continuous data were evaluated using the Mann-Whitney U test. Pearson's chi-square/Fisher's exact test was used for categorical data, and the Mann-Whitney U test was used for continuous data. 

Duration

June 1, 2020 to June 1, 2022

Outcome Measures

Primary: AKI occurrence within 7 days post-infusion (defined as an increase of ≥0.3 mg/dL within 48 h or serum creatinine (SCr) ≥1.5 times greater than baseline within seven days of administration)

Secondary: incidence of AKI in patients with baseline renal dysfunction (creatine clearance [CrCl]< 30 mL/ min or SCr ≥ 3 mg/dL), incidence of corrected calcium levels by day 7 post-infusion, incidence of hypophosphatemia on days 3 and 7 post infusion (defined as serum phosphorus <2.5 mg/dL), fever exceeding 100.4 °F within 24 hours post-infusion, hypocalcemia on days 3 and 7 post-infusion (defined as calcium levels <8.5 mg/dL)

Baseline Characteristics

Zoledronic acid (n= 158)

Pamidronate group (n= 33)

Male

Race

Caucasian

Black

70 (44.3%)

63 (39.9%)

8 (24.2%)

18 (54.5%)

Hypercalcemia of Malignancy

Results

Endpoint

Zoledronic acid (n= 158)

Pamidronate group (n= 33)

p-Value

Incidence of AKI

14 (8.9%)

3 (9.1%)

1.0

Incidence of AKI in patients with and without baseline renal dysfunction

Renal dysfunction

No baseline renal dysfunction

3 (14.3%)

11(8.2%)

2 (16.7%)

1 (4.7%)

0.322

0.000

Corrected calcium, day 7 post-infusion (<10.7 mg/dL)

Temperature, 24 hours post-infusion (>100.4 °F)

Hypophosphatemia, (<2.5 mg/dL)

Day 3 post-infusion

Day 7 post-infusion 

96 (60.8%)

31 (19.6%)

-

65 (41.1%)

33 (20.9%)

19 (57.6%)

5 (15.1%)

-

6 (18.1%)

5 (15.2%)

1.000

0.551

-

0.002

0.123

No differences were observed in the incidence of fever within 24 hours following bisphosphonate administration or hypophosphatemia on day 7 post-administration. However, a significant difference was noted in the incidence of hypophosphatemia on day 3, with a higher occurrence following zoledronic acid administration compared to pamidronate (average phosphorus = 2.38 vs. 2.86; p = 0.002).

Adverse Events

Study Author Conclusions

InpharmD Researcher Critique

The study's limitations include significantly different baseline characteristics between groups, such as more hypercalcemia of malignancy in the zoledronic acid group and higher baseline renal dysfunction in the pamidronate group. Additionally, the small sample size, uneven group distribution, and retrospective design, without formal power calculations, may have influenced the results.

Safety of Intravenous Bisphosphonates for the Treatment of Hypercalcemia in Patients With Preexisting Renal Dysfunction

Design

Retrospective analysis chart review

N= 113

Objective

To describe the safety and efficacy of pamidronate and zoledronic acid in treatment of hypercalcemia in patients with baseline renal dysfunction

Study Groups

Pamidronate (n= 55)

Zoledronic acid (n= 58)

Inclusion Criteria

Adult hospitalized patients ≥ 18 years old with CrCl < 60mL/min who developed hypercalcemia secondary to all causes and were treated with IV pamidronate or zoledronic acid

Exclusion Criteria

Received any previous bisphosphonate

Methods

This retrospective chart review investigated adult hospitalized patients with CrCl < 60 mL/min who developed hypercalcemia due to any cause and received IV pamidronate or zoledronic acid between 2014-2019.

Duration

Data collection: April 4, 2014 and April 30, 2019

Outcome Measures

Primary outcomes: All-grade serum creatinine (SCr) elevation

Secondary outcomes: Corrected serum calcium (CSC) decrease ≥1.0 mg/dL by day 7 of bisphosphonate administration, and normalization of CSC ≤10.5 mg/dL by days 10 and 30

Baseline Characteristics

Total (N= 113)

CrCl <30mL/min (n= 41)

CrCl ≥30mL/min (n= 72)

Age, years

Gender

Female

Male

71 (62.8%)

42 (37.2%)

24 (58.5%)

17 (41.5%)

47 (65.3%)

25 (34.7%)

Race

Caucasian

Black

other

57 (50.4%)

49 (43.4%)

7 (6.2%)

23 (56.1%)

15 (36.6%) 

3 (7.3%)

34 (47.2%)

34 (47.2%)

4 (5.6%) 

BMI (kg/m²)

 Indication for bisphosphonate

Hypercalcemia of malignancy

Hyperparathyroidism

Hypercalcemia of immobility

Other

93 (82.3%)

8 (7.1%)

7 (6.2%)

5 (4.4%) 

35 (85.4%)

1 (2.4%)

2 (4.9%)

2 (4.9%) 

57 (79.2%)

7 (9.7%)

5(6.9%)

3 (4.2%) 

 Degree of hypercalcemia at baseline

Mild (10.5-11.9 mg/dL)

Moderate (12-13.9 mg/dL)

Severe (>14 mg/dL)

27 (23.9%)

58 (51.3%)

28 (24.8%) 

10 (24.4%)

13 (31.7%)

13 (31.7%)

17 (23.6%)

15 (20.8%)

15 (20.8%)

 Bisphosphonate administered

Zoledronic acid

Pamidronate

58 (51.3%)

55 (48.7%)

8 (19.5%)

33 (80.5%)

50 (69.4%)

22 (30.6%)

 Baseline CSC (mg/dL)

Zoledronic acid

Pamidronate

13.3

13

14.3

13

13.1

13.1

SCr (mg/dL)

 Home medications

Calcium

Vitamin D

Thiazide diuretics

16 (14.2%)

27 (23.9%)

9 (8.0%)

8 (19.5%)

12 (29.3%)

3 (7.3%)

8 (11.1%)

15 (20.8%)

6 (8.3%)

Other hypercalcemia treatment

Furosemide

Calcitonin

54 (47.8%)

46 (40.7%)

23 (56.1%)

17 (41.5%)

31 (43.1%)

29 (25.7%)

CrCL, creatinine clearance; BMI, body mass index; CSC, corrected serum calcium; SCr, serum creatinine

Results

Endpoint

Pamidronate (n= 55)

Zoledronic acid (n= 58)

p-Value

all-grade serum creatinine (SCr) elevation

CSC decrease by 1.0 mg/dL by day 7

 CSC ≤ 10.5 mg/dL by day 10

 CSC ≤ 10.5 mg/dL by day 30

 Additional dose of bisphosphonate by day 30

Adverse Events

Common Adverse Events: hypocalcemia, phosphatemia, gastrointestinal side effects, and renal dysfunction

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: Not disclosed

Study Author Conclusions

The analysis suggests an association between IV bisphosphonates and increased rates of SCr elevations among patients with preexisting renal dysfunction. Future prospective studies are necessary to elucidate these findings

InpharmD Researcher Critique

Estimates of baseline renal function used serum creatinine levels at the start of bisphosphonate treatment, which may have been elevated due to acute effects like hypercalcemia and thus confounded the findings.

Safety and Efficacy of Intravenous Bisphosphonates for the Treatment of Hypercalcemia in Patients with Cancer and Baseline Renal Dysfunction

Design

Retrospective cohort study

N= 100

Objective

To compare the safety and efficacy of intravenous (IV) zoledronic acid and IV pamidronate in patients with hypercalcemia of malignancy with and without renal dysfunction

Study Groups

Normal kidney function (n= 50)

Reduced kidney function (n= 50)

Inclusion Criteria

Exclusion Criteria

Methods

Patients were categorized into two groups based on creatinine clearance (CrCl). Those with normal renal function (CrCl ≥60 mL/min) were matched 1:1 with those who had reduced kidney function (CrCl <60 mL/min). Hypercalcemia was defined as a corrected serum calcium level of ≥10.5 mg/dL, calculated using the formula: corrected serum calcium= serum calcium + 0.8 * (4-serum albumin) for patients with a serum albumin level of <4 g/dL. If no albumin value was available on the day the calcium was measured, the most recent value was used.

Duration

January 2012 to October 2020

Outcome Measures

Primary outcome: Complete response by day 10 and all-grade serum creatinine elevation by day 7

Secondary outcomes: Corrected serum calcium decrease by 1 mg/dL by day 7, relapsed or refractory hypercalcemia by day 30, number of days of hospitalization

Baseline Characteristics

Normal kidney function (n= 50) 

Reduced kidney function (n= 50)

Age, years (range)

Female

Race 

White

Black

Hispanic

Asian 

Unknown/other

29 (58%)

8 (16%)

10 (20%)

2 (4%)

1 (2%) 

33 (66%)

5 (10%)

8 (16%)

3 (6%)

1 (2%) 

BMI, kg/m² (range)

Bisphosphonate administered

Zoledronic acid

Pamidronate 

33 (66%)

17 (34%)

24 (48%)

26 (52%)

Degree of hypercalcemia at baseline

Mild (CSC 10.5-11.9 mg/dL)

Moderate (CSC 12-13.9 mg/dL)

Severe (CSC >14 mg/dL)

14 (28%)

27 (54%)

9 (18%)  

9 (18%)

24 (48%)

17 (34%) 

Baseline CSC, mg/dL (range)

Baseline SCr, mg/dL (range)

1.52 (0.84-4.72)

Home medications/supplements

Calcium

Vitamin D

Thiazide diuretics 

Calcitonin 

1 (2%)

4 (8%)

3 (6%) 

-

3 (6%)

12 (24%)

3 (6%)

1 (2%)

Other hypercalcemia treatment

Furosemide 

Calcitonin

22 (44%)

15 (30%)

24 (48%)

27 (54%) 

IV hydration 

Abbreviations: BMI, body mass index; CrCl, creatinine clearance; CSC, corrected serum calcium; SCr, serum creatinine

Results

Endpoint

Patients receiving zoledronic acid
(n= 57)

Patients receiving pamidronate
(n= 43)

p-Value

Corrected serum calcium
≤10.5 mg/dL by day 10

All-grade serum creatinine
elevation

Serum creatinine elevation by
grade

Grade 1

Grade 2

16 (28.1%)

4 (7.0%)

8 (18.6%)

4 (9.3%)

0.58

Hypocalcemia

8 (14%)

13 (30.2%)

Onset of serum creatinine increase,
days (range)

Corrected serum calcium decrease
by 1 mg/dL by day 7 (range)

Relapsed or refractory
hypercalcemia 

Days of hospitalization (range)

Adverse Events

Study Author Conclusions

No significant difference was observed in all-grade serum creatinine elevation or in complete response by day 10 between the 2 groups in relation to the use of bisphosphonate or baseline renal function. Future prospective studies are needed to inform the optimal bisphosphonate therapy in patients with severe renal dysfunction.

InpharmD Researcher Critique

The study's retrospective design and single-center setting limit its generalizability. Additionally, it was noted that concomitant hypercalcemia therapy might have differed between the groups based on the severity of hypercalcemia of malignancy or renal function, potentially confounding the results.