Bisphosphonate versus non-bisphosphonate treatment for hypercalcemia of malignancy in patients with renal dysfunction

Abstract

Background:

Bisphosphonates are the backbone of treatment for hypercalcemia of malignancy (HCM). However, concern regarding their safety in patients with renal dysfunction exists. The safety and effectiveness of bisphosphonates compared to other treatment options for HCM in the setting of renal dysfunction have not been evaluated.

Methods:

A retrospective cohort analysis of adult patients with HCM and renal dysfunction defined as a creatinine clearance (CrCl) <60 mL/min who received front-line bisphosphonate versus non-bisphosphonate therapy from 1/2015 to 4/2021 was conducted. The primary endpoint was the incidence of all-grade serum creatinine (SCr) elevation from baseline by day 30 from initial HCM-directed therapy. A multivariate logistic regression was conducted to examine predictors of worsening renal function.

Results:

Of 129 patients, 111 (86%) patients received bisphosphonates and 18 (14%) received non-bisphosphonate first-line HCM-directed therapy. All-grade SCr elevation occurred similarly between bisphosphonate and non-bisphosphonate groups, 27.9% versus 27.8% respectively (p = 0.99). Receipt of bisphosphonates did not significantly impact the incidence of all-grade SCr elevation (p = 0.195) while chronic kidney disease (CKD) at baseline did (p = 0.003).

Conclusions:

Bisphosphonates appear to be as safe as non-bisphosphonate therapy in patients with baseline renal dysfunction for the treatment of HCM.

Keywords

Bisphosphonates denosumab hypercalcemia of malignancy renal dysfunction

Introduction

Hypercalcemia of malignancy (HCM) occurs in 20%–40% of patients with malignancy, most commonly breast cancer, lung cancer, renal cell carcinoma, and multiple myeloma.^1,2 Symptoms range from mild (fatigue, anorexia, and constipation) to severe, with severe cases manifesting as neurological dysfunction (altered mental status or coma), arrhythmias, ventricular tachycardia, or renal insufficiency.^1–4 Mortality of patients diagnosed with HCM is as high as 50% within 30 days of diagnosis, regardless of treatment.⁵

Treatment of the primary malignancy is considered definitive therapy and should not be delayed when possible.⁶ Intravenous (IV) bisphosphonates are considered the mainstay of treatment due to their anti-resorptive properties via osteoclast inhibition.^1,7 Additional treatment modalities (IV hydration, calcitonin, loop diuretics, glucocorticoids) can be used adjunctly to correct volume depletion, increase filtration and promote a more rapid reduction in calcium while awaiting the onset of bisphosphonates.

Nephrotoxicity is a known adverse event of bisphosphonates and is dose- and infusion time-dependent.^8,9 Currently, limited data exist for use of bisphosphonates for HCM in patients with renal impairment, with pivotal trials excluding this patient population.¹⁰ Denosumab is typically reserved as a second-line treatment option, but it is often used first-line in patients not deemed to be bisphosphonate candidates. However, emerging literature has identified an increased risk of hypocalcemia with denosumab in patients with HCM and renal dysfunction.^11,12 While bisphosphonates may pose safety risks in patients with renal dysfunction, these risks can be mitigated with dose reductions and increased infusion times. It is unclear if alternate HCM treatment strategies are as effective as bisphosphonates and may have additional safety concerns of their own.

Almost all patients with HCM present with volume depletion and decreased filtration rate, and AKI can occur in up to 80% of patients with hypercalcemia.¹³ At the study site, bisphosphonates are used cautiously to treat HCM in patients with renal dysfunction, often with prolonged infusion times. However, some patients still receive non-bisphosphonate therapy due to concerns regarding safety in the setting of renal dysfunction. This study had two aims: (i) to evaluate safety outcomes in patients with renal dysfunction receiving bisphosphonate versus non-bisphosphonate therapy as front-line HCM treatment, and (ii) to assess effectiveness outcomes in patients with renal dysfunction who received bisphosphonates versus non-bisphosphonates.

Subjects and methods

Study design

This was a single-center retrospective cohort study conducted at an academic medical center. Ethics approval was obtained from the Institutional Review Board (IRB), and written informed consent was waived by the IRB given the retrospective nature of the study.

Adult patients 18 years and older who were treated in the inpatient or ambulatory setting for HCM between January 1, 2015 and April 30, 2021 were screened for inclusion. Patients were included if they had an active malignancy, hypercalcemia defined as a corrected serum calcium (CSC) ⩾10.5 mg/dL, and renal dysfunction defined as a creatinine clearance (CrCl) <60 mL/min. CrCl was calculated using the Cockroft-Gault equation, using actual body weight for BMI ⩽18.5 kg/m², ideal body weight for BMI 18.6–24.9 kg/m², or adjusted body weight for BMI ⩾25 kg/m². CrCl was used given the dosing for the medications of interest used CrCl as a metric for renal function. At the study site, the Jaffe reaction was performed on an ADVIA 1800 analyzer. Patients were excluded if they had a non-malignant cause of hypercalcemia (benign hyperparathyroidism, hyperthyroidism, adrenal insufficiency etc.), had received bisphosphonates for any indication within 90 days prior to the event, or were missing key laboratory values at two or more of the time points evaluated.

Patients were subsequently divided into two cohorts based on receipt of a bisphosphonate as front-line HCM-directed therapy. Patients in either cohort could have received other HCM-directed therapy (IV fluids, calcitonin, denosumab, loop diuretics, and/or glucocorticoids) as well as initiated treatment for their primary malignancy.

Study data were collected using the electronic medical record (EMR) and managed using the Research Electronic Data Capture (REDCap™) tool.¹⁴ Baseline data collected included demographics, malignancy characteristics, and renal function. HCM symptoms were considered severe if either altered mental status or cardiac arrhythmias were reported, all other symptoms were considered mild-moderate. CSC and CrCl were collected at baseline (defined as day of or 24 h prior to administration of initial HCM-directed therapy), and on days 7, 10, and 30 from the index date of initial HCM-directed therapy. Laboratory values within 72 h of the day 7 and day 10 timepoints and within 10 days of the day 30 timepoint were allowed. An additional CrCl was collected to characterize renal function prior to the HCM event. This CrCl value was obtained within 60 days prior to the event and at least 24 h prior to the baseline CrCl value. Renal dysfunction was categorized as either an acute kidney injury (AKI), chronic kidney disease (CKD), AKI on CKD, or none of the following. AKI was defined using the Kidney Disease Improving Global Outcomes (KDIGO) criteria of an increased creatinine level ⩾1.5 times baseline.¹⁵ CKD was defined using Common Terminology Criteria for Adverse Events Version 5 (CTCAE-V.5) criteria of a CrCl <60 mL/min.

Study endpoints

The primary endpoint was the incidence of all-grade SCr elevation from baseline by day 30 from initial HCM-directed therapy (according to CTCAE-V.5). Grade 1 SCr elevation was defined as an increase in SCr >1–1.5 times baseline or the upper limit of normal (ULN), grade 2 events were defined as SCr increases >1.5–3.0 times baseline or the ULN, grade 3 was defined as SCr increases >3.0–6.0 times baseline or the ULN, and grade 4 was defined as SCr elevations >6.0 times the ULN.

Secondary safety endpoints included all-grade hypocalcemia by day 30 (defined by CTCAE-V.5), osteonecrosis of the jaw (ONJ) within 1 year, and the need for calcium or vitamin D supplementation by day 30. Grade 1 hypocalcemia was defined as a CSC <lower limit of normal (LLN) to 8.0 mg/dL, grade 2 events were defined as CSC of <8.0 to 7.0 mg/dL, grade 3 was defined as CSC of <7.0 to 6.0 mg/dL; grade 4 was defined as CSC of <6.0 mg/dL. Secondary effectiveness endpoints included resolution of HCM (defined as CSC ⩽ 10.5 mg/dL) by day 30 and refractory HCM (defined as requiring additional doses of HCM-directed therapy by day 30). A post-hoc analysis evaluating the incidence of all-grade SCr elevation in patients with baseline CrCl <30 mL/min and ⩾30 mL/min was also performed.

Statistical analysis

Statistical analyses were performed using SPSS software, version 28.0 (SPSS, Version 28.0. Armonk, NY). Demographic data and disease characteristics were analyzed using descriptive statistics, and dichotomous variables were analyzed utilizing Fisher’s exact test or Pearson’s chi-squared test. Parametric continuous variables were analyzed using a two-tailed student’s t-test, and non-parametric continuous variables were compared using a Mann-Whitney U test. An alpha-level of 0.05 was considered statistically significant. A logistic regression was performed by considering baseline variables that were associated with the primary endpoint and had a p-value <0.1 on univariate analysis. A backwards stepwise regression was performed using this model to create the final adjusted model. Tests of collinearity were performed between the covariates of this adjusted model. In the case of co-linear variables, only one variable was chosen.

Results

A total of 1182 patients were identified and assessed for inclusion in this study. One thousand fifty-three were excluded, with the remaining 129 patients included in the analysis (Figure 1). The most common reasons for exclusion were not meeting CrCl or CSC criteria (n = 730), missing laboratory values on more than two timepoints (n = 164), and therapy received for a non-HCM indication (n = 152). Of the 129 patients included in the analysis, 111 patients received a bisphosphonate and 18 received non-bisphosphonate first-line HCM-directed therapy. Overall, baseline characteristics were similar between the two groups. Patients receiving bisphosphonates were more likely to have lymphoma (35.1% vs 11.1%, p = 0.04) and less likely to have breast cancer (9.0% vs 38.9%, p = 0.003). Patients receiving bisphosphonates also had a higher median CSC (13 vs 12.1 mg/dL, p = 0.02) and fewer patients with bone metastases (43.2% vs 72.2%, p = 0.02) at baseline (Table 1). Patients receiving bisphosphonates were less likely to have CKD (31.5% vs 55.6%, p = 0.047) and had a numerically higher incidence of AKI at presentation (31.5% vs 22.2%, p = 0.28). While not statistically significant, more patients who received bisphosphonates had severe HCM symptoms (31.5% vs 16.7%, p = 0.5).

Table 1.

Baseline demographics and disease characteristics.

	Bisphosphonate (n = 111)	Non-bisphosphonate (n = 18)	p-Value
Male, n (%)	61 (55)	6 (33.3)	0.09
Race, n (%)			0.84
White	95 (85.6)	15 (83.3)
Black	8 (7.2)	1 (5.6)
Asian	3 (2.7)	1 (5.6)
Other	5 (4.5)	1 (5.6)
Age, mean (years) ± SD	64.5 ± 11.9	68.0 ± 13.0	0.25
Baseline CSC^a, median (mg/dL) [range]	13.0 [10.7–19.3]	12.1 [10.5–15.5]	0.02*
Baseline CrCl^a, mean (mL/min) ± SD	38.5 ± 13.0	36.4 ± 12.7	0.51
Baseline CrCl <30 mL/min, n (%)	30 (27.0)	4 (22.2)	0.78
Type of renal injury, n (%)
AKI	39 (35.1)	4 (22.2)	0.28
CKD	35 (31.5)	10 (55.6)	0.047*
AKI on CKD	18 (16.2)	2 (11.1)	0.74
Malignancy, n (%)
Lymphoma	39 (35.1)	2 (11.1)	0.04*
Multiple myeloma	23 (20.7)	4 (22.2)	0.99
Breast	10 (9.0)	7 (38.9)	0.003*
SCC	12 (10.8)	2 (11.1)	0.99
Head/neck	5 (4.5)	1 (5.6)
Other	7 (6.3)	1 (5.6)
Prostate	4 (3.6)	1 (5.6)	0.53
RCC	3 (2.7)	0 (0)	0.99
NSCLC	2 (1.8)	1 (5.6)	0.37
Other	18 (16.2)	1 (5.6)	0.47
Stage of malignancy, n (%)			0.35
Stage 1	4 (3.6)	0 (0)
Stage 2	3 (2.7)	0 (0)
Stage 3	16 (14.4)	0 (0)
Stage 4	59 (53.2)	12 (66.7)
N/A^b	29(26.1)	6 (33.3)
Bone metastases, n (%)	48 (43.2)	13 (72.2)	0.02*
Presence of HCM symptoms, n (%)	88 (79.3)	13 (72.2)	0.54
Severity of HCM symptoms, n (%)			0.50
Mild-moderate	53 (47.7)	10 (55.6)
Severe	35 (31.5)	3 (16.7)
Non-bisphosphonate HCM treatment, n (%)
Denosumab	0 (0)	13 (72.2)
Calcitonin	55 (49.5)	8 (44.4)
Loop diuretics	8 (7.2)	0 (0)

AKI: acute kidney injury; CKD: chronic kidney disease; CrCl: creatinine clearance; CSC: corrected serum calcium; HCM: hypercalcemia of malignancy; NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma; SCC: squamous cell carcinoma; SD: standard deviation.

Prior to HCM-directed therapy. ^bR-ISS Staging for Multiple Myeloma excluded from traditional staging.

Statistically significant.

Within the bisphosphonate group, most patients received pamidronate (71.2%) at a dose of either 90 mg (50.6%) or 60 mg (46.8%) (Table 2). Pamidronate infusion times ranged from 90 to 720 min, with 120 min being the most common (54.4%). Zoledronic acid dosing ranged from 3 to 4 mg, with the majority of patients receiving 4 mg (68.8%). Infusion times ranged from 15 to 180 min, and 15 min was the most common infusion duration (68.8%) followed by 30 min (25%). Receipt of denosumab, calcitonin, and loop diuretics is described in Table 1.

Table 2.

Treatment details of those receiving bisphosphonates.

	Bisphosphonate (n = 111)
Zoledronic acid, n (%)	32 (28.8)
Pamidronate, n (%)	79 (71.2)
Pamidronate dose, n (%)
90 mg	40 (50.6)
60 mg	37 (46.8)
30 mg	2 (2.5)
Zoledronic acid dose, n (%)
4 mg	22 (68.8)
3.5 mg	3 (9.4)
3.3 mg	3 (9.4)
3 mg	4 (12.5)
Pamidronate infusion time, n (%)
<120 min	1 (1.3)
120–240 min	59 (74.7)
360–480 min	16 (20.3)
>480 min	3 (3.8)
Zoledronic acid infusion time, n (%)
15 min	22 (68.8)
30 min	8 (25.0)
>30 min	2 (6.3)

The primary endpoint of all-grade SCr elevation occurred similarly between bisphosphonate and non-bisphosphonate groups, 27.9% versus 27.8% respectively (p = 0.99). Grade 1 and 2 SCr elevation occurred in 25.2% and 2.7% of patients in the bisphosphonate group versus 27.8% and 0% of patients in the non-bisphosphonate group, respectively, with no grade 3 or 4 events in either group (Table 3). A multivariable logistic regression demonstrated receipt of bisphosphonates did not significantly impact the incidence of all-grade SCr elevation (OR 2.31 (0.651–8.171), p = 0.195) (Table 4). CKD prior to HCM was independently associated with all-grade SCr elevation (OR 3.74 (1.561–8.940), p = 0.003). Incidence of all-grade SCr elevation in patients with baseline CrCl <30 and ⩾30 mL/min was 16.7% versus 30.1% (p = 0.12).

Table 3.

Primary and secondary outcomes.

	Bisphosphonate (n = 111)	Non-bisphosphonate (n = 18)	p-Value
All-grade SCr elevation, n (%)	31 (27.9)	5 (27.8)	0.99
SCr elevation by grade, n (%)			0.86
Grade 1	28 (25.2)	5 (27.8)
Grade 2	3 (2.7)	0 (0)
All-grade hypocalcemia, n (%)	39 (35.1)	8 (44.4)	0.45
Hypocalcemia by grade, n (%)			0.07
Grade 1	23 (20.7)	3 (16.7)
Grade 2	14 (12.6)	2 (11.1)
Grade 3	2 (1.8)	3 (16.7)
Osteonecrosis of the jaw, n (%)	1 (0.9)	1 (5.6)	0.26
Need for IV/PO Ca or Vitamin D supplementation, n (%)	13 (11.7)	3 (16.7)	0.70
Resolution of HCM by day 30, n (%)	108 (97.3)	18 (100)	0.99
Refractory HCM requiring additional HCM-directed therapy, n (%)	43 (38.7)	5 (27.8)	0.37
Re-dosed bisphosphonate	17 (15.3)	0 (0)
Re-dosed denosumab	0 (0)	0 (0)
Re-dosed calcitonin	36 (32.4)	5 (27.8)

Ca: calcium; HCM: hypercalcemia of malignancy; SCr: serum creatinine.

Table 4.

Multivariable analysis of incidence of all-grade SCr elevations by day 30.

Variable	Univariable (p-value)	Multivariable (OR, 95% CI, p-value)
Received IV bisphosphonates	0.99	2.31 (0.651–8.171), p = 0.195
Received re-dose of IV bisphosphonate	0.04	0.14 (0.016–1.236), p = 0.077
CSC	0.004	0.75 (0.562–0.996), p = 0.047*
CKD prior to HCM	<0.001	3.74 (1.561–8.940), p = 0.003*

CKD: chronic kidney disease; CSC: corrected serum calcium; HCM: hypercalcemia of malignancy; SCr: serum creatinine.

Statistically significant.

Incidence of all-grade hypocalcemia by day 30 was 35.1% in the bisphosphonate group and 44.4% in the non-bisphosphonate group (p = 0.45). Grade 1 and 2 hypocalcemia events occurred in 33.3% in the bisphosphonate group versus 27.8% in the non-bisphosphonate group, respectively. While not statistically significant, grade ⩾3 hypocalcemia occurred in 1.8% of patients in the bisphosphonate group, and 16.7% of patients in the non-bisphosphonate group. Both groups had similar requirements for exogenous vitamin D or calcium supplementation, 11.7% in the bisphosphonate group and 16.7% in the non-bisphosphonate group (p = 0.7), and only one event of ONJ occurred in each group. Resolution of HCM by day 30 was similar between the bisphosphonate and non-bisphosphonate groups, 97.3% versus 100%, respectively (p = 0.99). Refractory HCM requiring additional treatment modalities within 30 days occurred in 38.7% in the bisphosphonate group and 27.8% in the non-bisphosphonate group (p = 0.37).

Discussion

To our knowledge, this is the first study evaluating the safety and effectiveness of bisphosphonates compared to other HCM treatment options in the setting of renal dysfunction. The standard of care for the treatment of HCM is bisphosphonate therapy, however concern existed regarding the safety of this treatment modality in patients with impaired renal function. Due to these safety concerns, patients with renal dysfunction were excluded from pivotal HCM trials and published outcomes of bisphosphonate therapy in this population of interest were limited to single-arm analyses. Here we demonstrate the safety and effectiveness of bisphosphonates for front-line treatment of HCM in the setting of renal dysfunction. Despite the high-risk population, incidence of all-grade SCr elevation was similar between groups, irrespective of bisphosphonate use.

Major et al.¹⁰ provided early data regarding the nephrotoxicity of bisphosphonates, with a 5.2% incidence of grade 3–4 SCr elevation reported in the zoledronic acid 8 mg group and 4% in the pamidronate 90 mg group. Results from this trial informed the standard practice of dosing zoledronic acid with no more than 4 mg for HCM treatment. This study had no CrCl requirement for inclusion, though patients with SCr >4.5 mg/dL were excluded from the trial. Information about baseline CrCl or outcomes in patients with renal dysfunction were not reported. Additionally, patients who were refractory to initial therapy (n = 15) could have received additional bisphosphonate doses as early as day 4, which may have further increased the risk of renal injury. This is inconsistent with current practice, in which bisphosphonates are typically re-dosed no earlier than day 7, due to the delayed onset of effect.¹⁶ Furthermore, zoledronic acid was infused over 5 min, whereas a 15-min minimum is now recommended in the prescribing information.¹⁶ Higher doses and shorter infusion times for zoledronic acid could have contributed to renal adverse events as bisphosphonate nephrotoxicity is related to peak effects. In contrast to the study by Major et al. our study population received bisphosphonates at standard or prolonged infusion times and included patients with SCr >4.5 mg/dL. However, there were few patients with SCr >4.5 mg/dL, four patients in the bisphosphonate group and one patient in the non-bisphosphonate group.^10,17

The safety of bisphosphonates in patients with CrCl <60 mL/min has been retrospectively examined in a single-arm study.¹⁷ Bisphosphonate dose reductions and prolonged infusion times were also utilized. The incidence of all-grade SCr elevation was 25.7% and comparable to the 27.9% incidence in our study. However, our study also found similar rates of SCr elevation in both bisphosphonate and non-bisphosphonate groups, suggesting that the incidence of SCr elevation may not be related to the receipt of bisphosphonates, but rather to baseline renal dysfunction prior to therapy. Our findings are further supported by the independent significance of CKD prior to HCM event (OR 3.74 (1.561–8.940), p = 0.003). Palmer et al. found no difference in all-grade SCr elevation among patients with baseline CrCl <30 versus ⩾30 mL/min (19.5% vs 29.2%, p = 0.3704) but did observe more high-grade SCr elevation in the CrCl <30 mL/min group (p = 0.0102). Our study also found no statistical difference in all-grade SCr elevation between those with baseline CrCl <30 versus ⩾30 mL/min (16.7% vs 30.1%, p = 0.12) and did not observe differences in grade of SCr elevation (p = 0.86), with no grade 3 or 4 SCr elevation observed in our study.

Patients in our analysis who received bisphosphonates had higher baseline median CSC (13.0 vs 12.1 mg/dL, p = 0.02), more severe HCM symptoms (31.5% vs 16.7%, p = 0.50), and increased incidence of AKI or AKI on CKD (51.3% vs 33.3%) compared to those who did not receive bisphosphonates. While not significant due to the limited sample size, these baseline characteristics indicated a more severe HCM presentation. Compared with Palmer’s study, baseline characteristics were similar, however Palmer’s study included patients with varying etiologies of hypercalcemia (82.3% HCM), while our study only included patients with HCM. Baseline CrCl was similar between these studies with a median CrCl of 34.9 mL/min in Palmer’s study and a mean of 38.5 mL/min in the bisphosphonate group of our study. Of note, our study had more re-doses of bisphosphonates by day 30 (15.4% vs 10.6%), which may suggest a more severe HCM presentation in our study cohort compared to Palmer et al.

Our findings showed that the use of bisphosphonates for HCM in patients with renal dysfunction was safe and efficacious, contrary to the findings of prior studies.^10,17 In this study, site-specific institutional protocols guided bisphosphonate selection, dosing, and infusion time based on CrCl. Dose reductions and prolonged infusion times may have decreased the incidence of SCr elevation, however no statistical differences were noted between different infusion times or doses used. The lack of observed difference could reflect appropriate infusion times for bisphosphonates based on CrCl, however the limited sample size of this analysis may also contribute to these findings. The benefit of the institution’s bisphosphonate dosing guidance compared to other strategies cannot be established from these data.

Similar effectiveness outcomes were observed between the cohorts, with almost 100% resolution of HCM by day 30 in both groups, and a low incidence of refractory HCM that was primarily driven by re-dosing of calcitonin. Incidence of all-grade hypocalcemia was markedly higher than reported in previous studies, and this was more pronounced in the non-bisphosphonate group (35.1% vs 44.1%, p = 0.45).^12,18 Hu et al. evaluated the treatment of HCM with denosumab at a dose of 120 mg denosumab weekly for 4 weeks followed by every 4 week dosing. This study had no CrCl cutoff for inclusion and found 6.06% of patients had grade 2 hypocalcemia by day 10. The difference in hypocalcemia incidence may be attributed to the duration patients were followed as our analysis followed patients through day 30. In addition, our study only included patients with renal dysfunction at baseline, who are at higher risk for this outcome. More recently, Cipriani conducted a retrospective study evaluating the use of denosumab 120 mg as the first-line treatment of HCM.¹⁹ This was a single-arm study of 15 patients, including 33% with renal dysfunction at baseline, defined as SCr >1.5× the pre-HCM baseline. The incidence of hypocalcemia was 47% (all grade 1 or 2 events), which was comparable to our non-bisphosphonate group with 44% all-grade hypocalcemia (including grades 1–3). Cipriani’s study evaluated laboratory values within 8 weeks of denosumab administration, which may explain the high incidence of hypocalcemia. In conjunction with our study, these data suggest that denosumab has a high incidence of hypocalcemia in patients with HCM, regardless of renal function.

Several limitations to this study should be noted. As a retrospective study, it is possible unmeasured confounding variables, such as selection bias in choice of HCM-directed therapy, as well as the specific anti-cancer regimen used, could have affected the outcomes. Baseline differences in primary malignancy and bone metastasis between groups may have skewed our results; certain HCM etiologies may respond to specific HCM-directed therapies better than others. In addition, patients in both groups received a broad selection of other HCM-directed therapies, which could obscure the true effectiveness and safety effects of the primary treatment modalities. However, the heterogeneity of treatment groups adds to the applicability of these data, as real-world patients with HCM are likely to receive a combination of therapies. A total of 56 patients (85.7% in the bisphosphonate group, 14.3% in non-bisphosphonate group) initiated malignancy-directed treatment within 14 days of HCM event. This potentially confounds our effectiveness outcomes since improvements in CSC may be attributed to malignancy-directed therapy, HCM-directed therapy, or both. In our analysis, effectiveness and safety endpoints were assessed based on laboratory values at specific timepoints, and SCr elevation or hypocalcemia occurring outside those timepoints may not have been detected. In addition other adverse effects of bisphosphonates such as proteinuria and electrolyte disorder (Fanconi syndrome) were not assessed, nor were concomitant nephrotoxic drugs. Our overall sample size was small, particularly in those who received non-bisphosphonate primary therapies, and as such definitive conclusions cannot be drawn. However, this is the largest data set to report on the safety of bisphosphonates in the setting of renal dysfunction and indicates their safety and effectiveness in this patient population.

Conclusion

Use of bisphosphonates was as safe and effective as non-bisphosphonate therapy for HCM in patients with baseline renal dysfunction. A small percentage of a high-risk patient group experienced worsening renal function after receiving bisphosphonates, which was also observed in the non-bisphosphonate group. While bisphosphonates were thought to be contraindicated in this population, these data suggest otherwise. CKD at baseline was the only variable found to impact SCr elevation, though prospective studies are needed to confirm our findings.

Supplemental Material

sj-pdf-1-jnp-10.1177_23993693231160612 – Supplemental material for Bisphosphonate versus non-bisphosphonate treatment for hypercalcemia of malignancy in patients with renal dysfunction

Supplemental material, sj-pdf-1-jnp-10.1177_23993693231160612 for Bisphosphonate versus non-bisphosphonate treatment for hypercalcemia of malignancy in patients with renal dysfunction by Christy J Khouderchah, Victoria R Nachar, Rachel L McDevitt and Allison J Schepers in Journal of Onco-Nephrology

Footnotes

Acknowledgements

N/A

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

Exempt status by Institutional Review Boards of the University of Michigan Medical School.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Christy J Khouderchah

Informed consent

N/A

Guarantor

AJS

Contributorship

N/A

Supplemental material

Supplemental material for this article is available online.

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