What do treatment guidelines for hypercalcemia or the literature say about the use of denosumab in the inpatient setting for patients with a creatinine clearance (CrCl) of less than 30 mL/min? What about the use of zoledronic acid in this same setting and CrCl cut-off?

Comment by InpharmD Researcher

Although studies specific to inpatient settings are limited, current societal guidelines and available data support denosumab as a reasonable option for patients with creatinine clearance (CrCl) less than 30 mL/min, particularly when bisphosphonates are contraindicated. Denosumab is not renally cleared and does not require dose adjustment in renal impairment; however, the risk of severe hypocalcemia is elevated in this population, especially without adequate calcium and vitamin D supplementation. In contrast, zoledronic acid is generally avoided in patients with CrCl below 35 ml/min due to its potential for renal toxicity, and its use requires caution even at higher GFR levels, with longer infusion times and close renal monitoring recommended when administered.

Background

The Endocrine Society clinical practice guidelines for the treatment of hypercalcemia of malignancy in adults, suggest a longer infusion over 30 to 60 minutes in patients with glomerular filtration rate (GFR) <60 mL/min and caution that zoledronic acid may cause kidney damage especially if the glomerular filtration rate is <30 to 35 mL/minute. The panel also recommends denosumab as an alternative to bisphosphonates in patients with severe renal impairment or those with bisphosphonate-refractory hypercalcemia. However, it is emphasized that patients with GFR<30 mL/min are at increased risk of hypocalcemia; therefore, close monitoring of serum calcium and consideration of dose reduction are recommended. [1]

Available review articles highlight that denosumab is not cleared by the kidney and has no renal toxicity, making it useful in patients with impaired renal function who cannot take bisphosphonates. It was also mentioned that because intravenous (IV) bisphosphonates may worsen renal insufficiency, their use is not recommended in patients with severe volume depletion or a CrCl<35 mL/min. The pharmacokinetic analyses of a 2012 open-label, multicenter trial revealed no statistically significant association between GFR and systemic exposure to denosumab as measured by AUC0–113 days or Cmax across renal function groups. Pharmacodynamically, denosumab led to a rapid and sustained suppression of serum C-telopeptide (sCTX1) levels, with median reductions of 65–85% maintained throughout the study period. Higher baseline sCTX1 values were observed in subjects with kidney failure, as expected, but relative reductions were comparable across groups. Hypocalcemia was the most clinically notable adverse event, manifesting in 15% of the cohort, with two subjects, both with severe chronic kidney disease (CKD) and without adequate calcium/vitamin D supplementation, experiencing serious events requiring IV calcium infusion. Importantly, none of the patients who received appropriate supplementation developed clinically significant hypocalcemia. These findings suggest that renal impairment does not necessitate denosumab dose adjustment but highlight the critical need for calcium and vitamin D supplementation, particularly in those with advanced kidney disease. [2], [3]

A 2024 presentation abstract describes a single-center, retrospective analysis that evaluated the renal safety and biochemical impact of denosumab therapy in adult patients with multiple myeloma (MM), particularly those with varying degrees of CKD who were either ineligible for bisphosphonates or had a history of renal impairment. The investigation included 97 MM patients treated at a tertiary academic center between January 1, 2016 and January 1, 2023. Baseline demographics encompassed a median age of 67 years (range, 42–96), with 47% of the cohort being male. Disease status at denosumab initiation categorized 26 patients as newly diagnosed on first-line therapy, 21 on salvage therapy, and 50 with stable disease on maintenance regimens. Paired pre- and post-treatment assessments revealed a statistically significant mean decrease in CrCl of 5.59 mL/min (p= 0.0086) following denosumab exposure, with more pronounced decline observed among those with CrCl ≥30 mL/min (mean decrease 7.56 mL/min; p= 0.0028) and those receiving monthly regimens (mean decrease 4.79 mL/min; p= 0.036). Patients with stable disease demonstrated a significant reduction in renal function (mean decrease 9.15 mL/min; p= 0.0002), whereas no meaningful change was noted in those with relapsed MM (p= 0.76). Additionally, 53% of the total cohort experienced at least one episode of hypocalcemia, a complication strongly associated with impaired baseline renal function (p= 0.019), especially among those receiving hemodialysis (89%). The authors concluded that denosumab demonstrated renal stability in patients with severe CKD receiving denosumab, though the observed declines in CrCl in patients with milder CKD warrant further investigation to delineate causality and clinical impact. [4]

Renal function impairment is a known potential side effect of bisphosphonates, including zoledronic acid, which necessitates careful consideration in patients with pre-existing renal conditions. Despite this, the consensus among experts suggests that the risks associated with its renal toxicity are generally manageable through regular monitoring of renal function through serum creatinine levels before each recommended dose. However, several underlying risk factors, including previous bisphosphonate therapy and use of nephrotoxic medications such as non-steroidal anti-inflammatory drugs, can potentially exacerbate the renal impairment condition. A 2011 expert review of the literature described the results from phase 3 clinical trials of patients with bone metastases from myeloma, breast, prostate, lung, or other solid tumors. Results from the clinical trials revealed that the incidence of renal impairment following zoledronic acid infusion during two years of 3-4 weekly infusions was approximately 10-15%, demonstrating an overall comparable renal safety profile of zoledronic acid compared to pamidronate. While renal toxicity remains a serious consideration in the use of zoledronic acid, adherence to guidelines on dosing and infusion, along with pre-treatment assessment and regular monitoring of renal function, allows for the safe use of zoledronic acid in a majority of patients. [5], [6], [7], [8]

A meta-analysis of three trials (N= 2,514) compared the 4-week versus 12-week reports of kidney dysfunction in patients with bone metastasis receiving zoledronic acid. A significant difference was not found (risk ratio [RR] 0.67; 95% confidence interval [CI] 0.39 to 1.15; p= 0.15), and both groups generally reported low rates of kidney dysfunction (2.45% in the 4-week group and 1.68% in the 12-week group). [9]

Reports from a French adverse event database revealed that up to July 2004, seven patients (aged 52-70 years) with MM or different types of metastatic cancer experienced renal impairment during treatment with zoledronic acid. Four of these patients with different cancer-related histories (one having bone metastasis) developed acute renal impairment with renal toxicity while on zoledronic acid, whereas three of them experienced acute deterioration of preexisting chronic renal failure. The duration of zoledronic acid therapy varied (1-120 days). The mean duration of renal failure was 40 days, with three cases having recovered completely. Death occurred in two of the patients. However, owing to the underlying comorbidities and terminal illness, the causal association of death with zoledronic acid therapy can not be ascertained. While renal toxicity of zoledronic acid appears to be both dose and infusion-time-dependent, close and regular monitoring of renal function is highly advised, particularly in patients with preexisting risk factors or impaired renal function. [10]

Relevant Prescribing Information

Prolia (denosumab injection)
Renal impairment: No dose adjustment is necessary in patients with renal impairment. Patients with advanced chronic kidney disease (eGFR <30 mL/min/1.73 m2), including dialysis-dependent patients, are at greater risk of severe hypocalcemia. The presence of underlying chronic kidney disease-mineral bone disorder markedly increases the risk of hypocalcemia. [12]

Zoledronic acid injection
Renal impairment: Zoledronic Acid Injection is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment. There are no safety or efficacy data to support the adjustment of the Zoledronic Acid Injection dose based on baseline renal function. Therefore, no dosage adjustment is required in patients with a creatinine clearance of greater than or equal to 35 mL/min. Risk of acute renal failure may increase with underlying renal disease and dehydration secondary to fever, sepsis, gastrointestinal losses, diuretic therapy, advanced age, etc. [13]

Literature Review

A search of the published medical literature revealed 9 studies investigating the researchable question:

What do treatment guidelines for hypercalcemia or literature say about the use of denosumab in the inpatient setting for patients with a crcl of less than 30 mL/min? what about the use of zoledronic acid in this same setting and crcl cut off?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-9 for your response.

Safety of Intravenous Bisphosphonates for the Treatment of Hypercalcemia in Patients with Preexisting Renal Dysfunction
Design	Retrospective analysis N= 113
Objective	To describe the safety and efficacy of pamidronate and zoledronic acid (ZA) in the treatment of hypercalcemia in patients with baseline renal dysfunction
Study Groups	Zoledronic acid (n= 58) CrCl <30 mL/min (n= 41) CrCl ≥30 mL/min (n= 72)
Inclusion Criteria	Adult hospitalized patients ≥18 years old with creatinine clearance (CrCl) <60 mL/min who developed hypercalcemia secondary to all causes and were treated with intravenous (IV) pamidronate or zoledronic acid
Exclusion Criteria	Received any previous bisphosphonate
Methods	Participants were picked utilizing institutional data analytics software on the basis of documented administration of IV zoledronic acid or pamidronate. Hypercalcemia was defined by a corrected serum calcium (CSC) level ≥10.5 mg/dL, and renal dysfunction was defined as CrCl <60 mL/min. Data were collected on bisphosphonate treatment day and then days 7, 10, and 30 post-administration. Of note, only results for zoledronic are reported within this table.
Duration	Charts reviewed: April 4, 2014 to April 30, 2019
Outcome Measures	Primary: all-grade SCr elevation based on severity according to Common Terminology Criteria for Adverse Events Version 5 (CTCAE-V.5) Safety: CSC decrease ≥1.0 mg/dL by day 7 of index date of bisphosphonate administration; normalization of CSC ≤10.5 mg/dL by day 10; CSC normalization of ≤10.5 mg/dL by day 30; incidence of refractory hypercalcemia or hypocalcemia by day 30 of index date of bisphosphonate administration and osteonecrosis of the jaw (ONJ) up to 1 year after index date of bisphosphonate administration
Baseline Characteristics		CrCl <30 mL/min (n= 41)	CrCl ≥30 mL/min (n= 72)
	Age, years (range)	67 (31-80)	67 (38-88)
	Female	24 (58.5%)	47 (65.3%)
	Race White Black Other	23 (56.1%) 15 (36.6%) 3 (7.3%)	34 (47.2%) 34 (47.2%) 4 (5.6%)
	Body mass index, kg/m² (range)	25.6 (15.7-46.6)	24.8 (11.8-47.1)
	Indication for bisphosphonate HCM Hyperparathyroidism HCI Other	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 Mild (10.5-11.9 mg/dL) Moderate (12-13.9 mg/dL) Severe (> 14 mg/dL)	10 (24.4%) 13 (31.7%) 13 (31.7%)	17 (23.6%) 15 (20.8%) 15 (20.8%)
	Bisphosphonate administered Zoledronic acid Pamidronate	8 (19.5%) 33 (80.5%)	50 (69.4%) 22 (30.6%)
	Baseline CSC, mg/dL (range) Zoledronic acid Pamidronate	14.3 (12.2-15.3) 13 (10.6-20.4)	13.1 (10.4-20.1) 13.1 (11.1-18.8)
	SCr, mg/dL (range)	3 (1.33-8.52)	1.3 (0.7-2.3)
	Home medications Calcium Vitamin D Thiazide diuretics	8 (19.5%) 12 (29.3%) 3 (7.3%)	8 (11.1%) 15 (20.8%) 6 (8.3%)
	Other hypercalcemia treatment Furosemide Calcitonin	23 (56.1%) 17 (41.5%)	31 (43.1%) 29 (25.7%)
	HCM: Hypercalcemia of malignancy, HCI: Hypercalcemia of immobility
Results	Endpoint	Zoledronic acid (n= 58)	CrCl <30 mL/min (n= 41)	CrCl ≥30 mL/min (n= 72)
	All-grade SCr increase All ZA doses 3-3.5 mg ZA dose 4 mg ZA dose 15-minute ZA infusion 60-minute ZA infusion	13/58 (22%) 2/9 (22%) 12/49 (24%) 11/44 (25%) 3/14 (21%)
	CSC ≤10.5 mg/dL by day 10 All ZA doses 3-3.5 mg ZA dose 4 mg ZA dose 15-minute ZA infusion 60-minute ZA infusion	37/58 (63.8%) 5/9 (56%) 32/49 (65% 30/44 (68%) 7/14 (50%)	35 (85.4%)	57 (79.2%)
	Hypocalcemia Grade 1 Grade 2 Grade 3	9 (15.5%) 5 (8.6%) 1 (1.7%)	8 (19.5%) 10 (24.4%) 1 (2.4%)	10 (13.9%) 6 (8.3%) 1 (1.4%)
	CSC decrease by 1.0 mg/dL by day 7	48 (82.8%)	35 (85.4%)	57 (79.2%)
	CSC ≤10.5 mg/dL by day 30	34 (58.6%)*	33 (80.5%)**	44 (61.1%)
	* Significantly more patients who received zoledronic acid achieved CSC ≤10.5 mg/dL by day 30 compared to patients who received pamidronate (78.2%). **Significantly more patients achieved CSC ≤10.5 mg/dL by day 30 in the subgroup of CrCl <30 mL/min compared to the subgroup of CrCl ≥30 mL/min.
Adverse Events	Osteonecrosis of the jaw did not occur in any groups; no other adverse effects were 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	This study was unable to distinguish outcome differences in acute and chronic kidney renal dysfunction. This study does not clearly identify whether zoledronic acid is an effective treatment for hypercalcemia.

References:

Palmer S, Tillman F 3rd, Sharma P, et al. Safety of Intravenous Bisphosphonates for the Treatment of Hypercalcemia in Patients With Preexisting Renal Dysfunction. Ann Pharmacother. 2021;55(3):303-310. doi:10.1177/1060028020953501

Safety and Efficacy of Intravenous Bisphosphonates for the Treatment of Hypercalcemia in Patients with Cancer and Baseline Renal Dysfunction
Design	Retrospective cohort study N= 18
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	Zoledronic acid in severe renal dysfunction (n= 5) Pamidronate in severe renal dysfunction (n= 13)
Inclusion Criteria	Age ≥18 years or older, hospitalized at the medical center
Exclusion Criteria	Allergic reaction or sensitivity to bisphosphonates, received IV or oral bisphosphonates within the last 90 days
Methods	In the primary analysis of the study, 100 patients were divided (1:1) into 2 groups: normal renal function (CrCl ≥ 60 mL/min) or reduced renal function (CrCl < 60 mL/min). An additional subanalysis was conducted in patients receiving zoledronic acid with severe renal dysfunction (CrCl < 30 mL/min) and will be the focus of the table. Baseline serum creatinine values were determined as the most recent value prior to bisphosphonate administration.
Duration	Data collection: January 1, 2012 to October 1, 2020
Outcome Measures	Corrected serum calcium, relapse or refractory hypercalcemia, safety
Baseline Characteristics		Study population (N= 100)
	Age, years	60
	Female	35%
	White	62%
	Body mass index, kg/m²	24.81
	Baseline SCr, mg/dL	1.2
Results	Endpoint	Zoledronic acid in severe renal dysfunction (n= 5)	Pamidronate in severe renal dysfunction (n= 13)
	Corrected serum calcium ≤ 10.5 mg/dL by day 10	4 (80%)	11 (84.6%)
	Corrected serum calcium decrease by 1 mg/dL by day 7	5 (100%)	12 (92.3%)
	Relapsed or refractory hypercalcemia	1 (20%)	1 (7.7%)
	Safety All-grade serum creatinine elevation Hypocalcemia	2 (40%) 0	2 (15.4%) 6 (46.2%)
Adverse Events	See above
Study Author Conclusions	Future prospective studies are needed to inform the optimal bisphosphonate therapy in patients with severe renal dysfunction.
InpharmD Researcher Critique	Use of zoledronic acid in severe renal dysfunction was limited to a subanalysis which requires validation in future studies. Results were similar to pamidronate, but its efficacy versus an untreated group was not established.

References:

Hsu EH, Beechinor R. Safety and Effiacy of Intravenous Bisphosphonates for the Treatment of Hypercalcemia in Patients with Cancer and Baseline Renal Dysfunction. JHOP. 2022; 12(4).

Risk of renal failure in cancer patients with bone metastasis treated with renally adjusted zoledronic acid
Design	Retrospective observational chart review N= 220 (1,472 doses)
Objective	To evaluate the incidence of acute renal failure (ARF) in patients with mild to moderate renal dysfunction, receiving renally adjusted zoledronic acid (ZA) and compare it to patients with normal baseline renal function, receiving standard-dose ZA.
Study Groups	Normal (n= 184) Impaired (n= 36)
Inclusion Criteria	Ages 18-89 years, documented metastatic bone disease, received at least one dose of ZA, baseline serum creatinine (SCr) and at least one follow-up SCr available
Exclusion Criteria	Treatment of hypercalcemia of malignancy, received ZA within 14 days of a previous dose, documented episode of ARF within 1 month
Methods	Data were identified of patients meeting criteria at the VA North Texas Health Care System via pharmacy records. Patients were divided into two groups: a normal group with baseline creatinine clearance (CrCl) > 60 mL/min and standard ZA dose, and an impaired group with baseline CrCl of 30-60 mL/min and renally adjusted ZA dose. ZA was administered at 4 mg until 2005, when labeling changes for patients with impaired renal function (30-60 mL/min) changed, and the manufacturer recommended a dose of 3-3.5 mg for patients with pre-existing renal dysfunction. Incidence of ARF was defined as an SCr increase of 0.5 mg/dL or 1.0 mg/dL from a baseline SCr of <1.4 mg/dL or ≥ 1.4 mg/dL, respectively.
Duration	August 20, 2001 to September 30, 2009
Outcome Measures	Incidence of ARF
Baseline Characteristics		Normal (n= 184)	Impaired (n= 36)
	Age (median), years*	64	77
	Weight (median), kg	83.4	79.1
	Baseline SCr (median), mg/dL*	0.9	1.4
	Baseline CrCl (median), mL/min*	82.7	49.7
	ZA dose (median), mg 4 mg, n (%) 3.5 mg, n (%) 3.3 mg, n (%) 3 mg, n (%)	4 184 (100%) - - -	3.4 - 18 (50%) 16 (44%) 2 (6%)
	ZA infusions per patient, mean*	7.1	4.6
	Concomitant nephrotoxic agents, %	69.6%	75%
	*p< 0.05
Results	Endpoint	Normal (n= 184)	Impaired (n= 36)
	ARF based on SCr ARF incidence, n (%) Mean time to ARF, months	38 (20.7%) 6.1	7 (19.4%) 6.1
	ARF based on CrCl ARF incidence, n (%) Mean time to ARF, months	72 (39.1%) 5.4	15 (41.7%) 4.1
	Dialysis, n (%)	1 (0.5%)	1 (2.8%)
	Maximum change in SCr, mean	0.39	0.70
	Incidence of skeletal-related events	10.3%	13.9%
	There was no difference in the incidence of ARF based on SCr or CrCl between the groups. Skeletal-related events were defined as the following: pathological fracture, spinal cord compression, radiation therapy to bone, or surgery to bone. Regression analysis identified receipt of greater than 3 ZA infusions was a significant factor influencing the incidence of ARF based on SCr (odds ratio, 2.01; 95% CI, 1.02-3.96). Univariate and multivariate analyses identified age greater than 65 as another risk factor associated with ARF based on CrCl.
Adverse Events	N/A
Study Author Conclusions	The incidence of ARF is similar between patients in the normal group and impaired group when the ZA dose is renally adjusted.
InpharmD Researcher Critique	Due to label changes, use of 4 mg was not explored in patients with renal dysfunction. Additionally, this study did not determine safety nor efficacy of zoledronic acid administration in patients with acute kidney injury; thus, these results may not be extrapolatable to the current inquiry.

References:

Shah SR, Jean GW, Keisner SV, Ussery SM, Dowell JE. Risk of renal failure in cancer patients with bone metastasis treated with renally adjusted zoledronic acid. Support Care Cancer. 2012;20(1):87-93. doi:10.1007/s00520-010-1067-7

Renal safety of zoledronic acid for osteoporosis in adults 75 years and older
Design	Retrospective, cross-sectional, pre-post analysis N= 558 zoledronic acid infusions (327 patients)
Objective	To examine renal function change in older adults with osteoporosis, treated with zoledronic acid
Study Groups	Pre-infusion (n= 558) Post-infusion (n= 558)
Inclusion Criteria	Aged≥ 75 years; diagnosis of osteoporosis; received at least one 5 mg/100 mL dose of intravenous (IV) zoledronic acid at a rate of 200–400 mL/h; at least one serum creatinine (SCr) documentation in the year before the zoledronic acid infusion and in the year following the infusion that was not drawn on the same day as the infusion
Exclusion Criteria	Received > one dose of zoledronic acid in 12 months; received a zoledronic acid dose other than 5 mg; diagnosis of cancer or a neoplasm of unknown behavior
Methods	Data from the period of zoledronic acid infusion were collected via electronic health records, and changes in serum creatinine (SCr) before and after zoledronic acid infusions were analyzed. If a patient had multiple infusions separated by 12 months or more, data from each infusion was included. All levels were reviewed if multiple SCr levels were drawn in the year following the zoledronic acid infusion. However, only the level closest to a year after the infusion was used in the pre-post analysis. Acute kidney injury (AKI) was defined as stage 1 which equates to ≥0.3 mg/dL or ≥1.5 × baseline increase in SCr.
Duration	One year
Outcome Measures	Primary: Mean change in SCr from baseline to after the zoledronic acid infusion Secondary: other renal function parameters (e.g., creatinine clearance [CCr], glomerular filtration rate)
Baseline Characteristics		Patients age≥75 (n= 558)	Patients age ≥ 75 with CCr < 35 mL/min (n= 25)
	Age, years	80 ± 3.4	82 ± 3.7
	Female	92.8%	100%
	White	99.6%	100%
	Body mass index, kg/m²	25.6 ± 4.7	21.4 ± 2.8
	Infusion time 15 min >15 min	94.3% 5.7%	96% 4%
	Renal function Serum creatinine, mg/dL CrCl*, mL/min Glomerular filtration rate (GFR), mL/min	0.85 ± 0.19 56.7 ± 14.9 72.0 ± 14.5	1.09 ± 0.17 30.8 ± 4.1 52.1 ± 8.3
	*CCr estimated using Cockcroft-Gault equation
Results	Endpoint	Pre-infusion (n= 558)	Post-infusion (n= 558)	p-value
	Serum creatinine, mg/dL	0.85 ± 0.19	0.84 ± 0.19	0.005
	CrCl, mL/min	56.7 ± 14.9	57.6 ± 15.4	-
	GFR, mL/min	72.0 ± 14.5	73.1 ± 14.4	-
	Sustained creatinine increase ≥0.3 mg/dL or ≥1.5 × baseline	-	0	-
	Transient creatinine increase ≥0.3 mg/dL or ≥1.5 × baseline	-	1.4%	-
	Mean SCr decreased by 0.01 mg/dL in the year following zoledronic acid infusions (p= 0.005). AKI occurred in 1.4% of patients and all had CCr > 45 mL/min; 4.5% of patients had CCr < 35 mL/min and none experienced an AKI.
Adverse Events	N/A
Study Author Conclusions	There was no clinically relevant change in SCr after zoledronic acid infusions. Risk of nephrotoxicity was low and similar to risk seen in randomized trials occurring in younger patients. Kidney function estimates were dramatically lower using the Cockcroft-Gault (CG) equation in comparison to CKD-EPI. We believe the use of the CG equation in this population may be inappropriately limiting our ability to use zoledronic acid for treatment of osteoporosis in older adults but more evidence is necessary.
InpharmD Researcher Critique	Aside from limitations based on the study's single-center, retrospective, observational nature, the included patients were primarily white women, potentially limiting the generalizability of the results. Moreover, no data were available on the potential risk factors for AKI, such as concurrent nephrotoxic medications at baseline.

References:

Fixen CW, Fixen DR. Renal safety of zoledronic acid for osteoporosis in adults 75 years and older. Osteoporos Int. 2022;33(11):2417-2422. doi:10.1007/s00198-022-06499-4

Immobilization-induced severe hypercalcaemia successfully treated with reduced dose of zoledronate in a maintenance haemodialysis patient
Design	Case report
Case presentation	A 43-year-old female receiving maintenance hemodialysis who was hospitalized for ileus associated with encapsulating peritoneal sclerosis. She had received peritoneal dialysis for 6 years and hemodialysis for 3 years and had had a living-related-donor kidney transplant for 21 years. Upon admission, her serum calcium level was elevated at 2.55 mmol/L, which further progressed to 4.23 mmol/L, despite treatment with low-calcium dialysate baths. Her case was complicated by a consciousness disorder, and the patient was diagnosed with immobilization-induced hypercalcemia after ruling out other causes of hypercalcemia, such as hyperparathyroidism and vitamin D intoxication. A reduced dose of zoledronate (3 mg) was administered intravenously, leading to a rapid decrease in serum calcium level; her corrected serum calcium level was 2.23 mmol/L 14 days after zoledronate treatment and remained at 2.13–2.63 mmol/L thereafter. Three months later, she developed another hypercalcemia (2.05 mmol/L) but was successfully treated with a reduced dose of zoledronate (2 mg), with no adverse effects. The patient was subsequently transferred to another institution for maintenance hemodialysis and rehabilitation.
Study Author Conclusions	Based on the findings, the authors concluded that reduced-dose zoledronate is a safe and useful treatment option for acute and transient hypercalcemia in hemodialysis patients. However, the findings are limited to a single patient experience, limiting the generalizability to the general hemodialysis population.

References:

Yamada S, Arase H, Tachibana S, et al. Immobilization-induced severe hypercalcaemia successfully treated with reduced dose of zoledronate in a maintenance haemodialysis patient. Nephrology (Carlton). 2018;23(10):963-964. doi:10.1111/nep.13246

Successful treatment with anti-tuberculous drugs and zoledronate of hypercalcemia due to calcitriol overproduction in a patient undergoing maintenance dialysis complicated by tuberculous pleuritis
Design	Case report
Case presentation	An 80-year-old woman undergoing peritoneal dialysis for end-stage kidney disease (ESRD) secondary to IgA nephropathy two years prior presented with persistent pyrexia and was hospitalized. Despite a diagnostic workup and negative bacterial cultures for a massive progressive left hydrothorax, the origin of pyrexia was not discovered. Five months earlier, she was discharged after resolution of multidrug-resistant (MDR) Staphylococcus epidermidis bacterial peritonitis with a serum calcium of 9.8 mg/dL. The patient's consciousness on admission was slightly impaired, and her laboratory values were as follows: serum C-reactive protein 12 mg/dL, corrected serum calcium 15.6 mg/dL, and serum calcitriol level 62.6 pg/mL. Notably, the patient was not prescribed calcium-based phosphate binders or vitamin D receptor activators. Imaging found multiple bilateral foci in pleural cavitis. Eventually, the patient was diagnosed with tuberculosis pleuritis complicated by pyrexia and hypercalcemia secondary to extrarenal overproduction of calcitriol, after a positive T-SPOT test for blood and pleural effusion samples. Therapy with isoniazid, rifampicin, and ethambutol was initiated, as well as a reduced dose of zolendronate (3 mg/kg) due to altered mental status caused by the hypercalcemia. The patient's mental status returned to normal, as did her serum calcium levels, and after two months, pyrexia was resolved. Serum calcium level was 9.4 mg/dL and serum calcitriol level was 9.2 pg/mL upon follow-up at two months.
Study Author Conclusions	In the context of hemodialysis, hypercalcemia is often observed due to uremic secondary hyperparathyroidism and medications such as vitamin D derivatives. In our patient, serum PTH levels were suppressed, and calcitriol levels were elevated. We conclude that intravenous zoledronate administration may be useful for treating hypercalcemic crises and that extrapulmonary tuberculosis should be considered as a cause of persistent pyrexia and hydrothorax.

References:

Yamada S, Kitazono T, Nakano T. Successful treatment with anti-tuberculous drugs and zoledronate of hypercalcemia due to calcitriol overproduction in a patient undergoing maintenance dialysis complicated by tuberculous pleuritis. Ther Apher Dial. 2024;28(2):333-335. doi:10.1111/1744-9987.14084

sphosphonate Versus Non-Bisphosphonate Treatment for Hypercalcemia of Malignancy in Patients with Renal Dysfunction
Design	Single center retrospective cohort study N= 129
Objective	To evaluate safety outcomes in patients with renal dysfunction receiving bisphosphonate versus non-bisphosphonate therapy as front-line hypercalcemia of malignancy (HCM) treatment, and to assess effectiveness outcomes in patients with renal dysfunction who received bisphosphonates versus non-bisphosphonates
Study Groups	Bisphosphonate (n= 111) Non-bisphosphonate (n= 18)
Inclusion Criteria	Patients 18 years and older who were treated in the inpatient or ambulatory setting for hypercalcemia of malignancy (HCM) with an active malignancy, hypercalcemia defined as a corrected serum calcium (CSC) ≥10.5mg/dL, and renal dysfunction defined as a creatinine clearance (CrCl) <60mL/min
Exclusion Criteria	Patients with 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
Methods	Eligible patients were identified by electronic medical records. Patients were then divided into 2 cohorts based on bisphosphate use. Other HCM therapies such as fluids, calcitonin, denosumab, loop diuretics, and/or glucocorticoids, and treatment for their primary malignancy were allowed in both cohorts. Data was collected for baseline and on day 7, 10, and 30 from initiating therapy. Creatinine clearance 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. Acute kidney injury (AKI) was defined by increased creatinine level ≥ 1.5 times baseline. All-grade SCr elevations were graded according to CTCAE-V.5: Grade 1 SCr elevation: increase in SCr >1–1.5 times baseline or the upper limit of normal (ULN); Grade 2 events: SCr increases >1.5–3.0 times baseline or the ULN; Grade 3: SCr increases >3.0–6.0 times baseline or the ULN; Grade 4: SCr elevations >6.0 times the ULN. A post-hoc analysis evaluated the incidence of all-grade SCr elevation in patients with baseline CrCl <30mL/min and ≥ 30mL/min.
Duration	Treatment received between January 1, 2015 and April 30, 2021
Outcome Measures	Primary: incidence of all-grade SCr elevation from baseline by day 30 from initial HCM-directed therapy (according to CTCAE-V.5) Secondary: resolution of HCM by day 30 and refractory HCM Secondary safety: all-grade hypocalcemia by day 30, osteonecrosis of the jaw (ONJ) within 1 year, and the need for calcium or vitamin D supplementation by day 30
Baseline Characteristics		Bisphosphonate (n= 111)	Non-bisphosphonate (n= 18)
	Age, years ± SD	64.5 ± 11.9	68.0 ± 13.0
	Male	55%	33.3%
	CSC, mg/dL (median [range]) CrCl, mL/min (mean ± SD)	13.0 [10.7–19.3] 38.5 ± 13.0	12.1 [10.5–15.5] 36.4 ± 12.7
	CrCl <30 mL/min	27%	22.2%
	Non-bisphosphonate HCM treatment Denosumab Calcitonin Loop diuretics	0% 49.5% 7.2%	72.2% 44.4% 0%
	Zoledronic acid use Dose 4 mg 3.5 mg 3.3 mg 3 mg Infusion time (Range: 15 to 180 min) 15 min 30 min > 30 min	32 of 111 (28.8%) 22 (68.8%) 3 (9.4%) 3 (9.4%) 4 (12.5%) 22 (68.8%) 8 (25%) 2 (6.3%)	N/A
	CrCl: creatinine clearance; CSC: corrected serum calcium; HCM: hypercalcemia of malignancy; SD: standard deviation * Prior to HCM-directed therapy
Results	Endpoint	Bisphosphonate (n= 111)	Non-bisphosphonate (n= 18)	p-Value
	All-grade SCr elevation at day 30 Grade 1 Grade 2 Grade 3-4	27.9% 25.2% 2.7% 0%	27.8% 27.8% 0% 0%	p=0.99
	Multivariable logistic regression: All-grade SCr elevation stratified by baseline characteristics
		All-Grade SCr Elevation (n= 36)	No all-grade SCr elevation (n= 93)	p=Value
	CrCl, mL/min < 30 ≥ 30	16.7% 83.3%	30.1% 69.9%	0.12
	Type of Renal Injury AKI CKD AKI on CKD	5 (13.9%) 21 (58.3%) 3 (8.3%)	38 (40.9%) 24 (25.8%) 17 (18.3%)	0.004* <0.001* 0.162
	Received Zoledronic Acid Dose 4 mg <4 mg Infusion Time 15 min > 15 min	8 (22.2%) 4 (11.1%) 4 (11.1%) 5 (13.9%) 3 (8.3%)	24 (25.8%) 18 (19.4%) 6 (6.5%) 17 (18.3%) 7 (7.5%)	0.67 0.73 0.68
	AKI: acute kidney injury; CKD: chronic kidney disease; CrCl: creatinine clearance Multivariable logistic regression demonstrated receipt of bisphosphonates did not significantly impact the incidence of all-grade SCr elevation (OR 2.31, 95% CI 0.651–8.171, p=0.195) All-grade SCr elevations (n= 36): Baseline CrCl (mL/min) <30: 16.7% Baseline CrCl (mL/min) ≥30: 83.3% Baseline CKD was independently associated with all-grade SCr elevation (OR 3.74, 95% CI 1.561–8.940, p=0.003) Incidence of all-grade SCr elevation in patients with baseline CrCl <30 and ≥30mL/min was 16.7% versus 30.1% (p=0.12) Resolution of HCM by day 30 was similar between the bisphosphonate and non-bisphosphonate groups, 97.3% versus 100%, respectively (p=0.99)
Adverse Events	See results
Study Author Conclusions	Bisphosphonates appear to be as safe as non-bisphosphonate therapy in patients with baseline renal dysfunction for the treatment of HCM
InpharmD Researcher Critique	There are inherent limitations of a small retrospective study. Additionally, baseline differences, concurrent therapies, and heterogeneity of the treatment groups may impact results. Results do not evaluate relationships between renal function values and zoledronic acid.

References:

Khouderchah CJ, Nachar VR, McDevitt RL, Schepers AJ. Bisphosphonate versus non-bisphosphonate treatment for hypercalcemia of malignancy in patients with renal dysfunction. Journal of Onco-Nephrology. 2023;7(2):49-56. doi:10.1177/23993693231160612

Use of denosumab to treat refractory hypercalcemia in a peritoneal dialysis patient with immobilization and tertiary hyperparathyroidism
Design	Case report
Case presentation	A 71-year-old Caucasian male with a complex medical history including chronic kidney disease (CKD) due to lithium-induced and diabetic nephropathy, underwent continuous ambulatory peritoneal dialysis (PD) starting in April 2015. Over the course of his treatment, he experienced worsening hyperparathyroidism with a concerning rise in intact parathyroid hormone (PTH) levels and increasing calcium and alkaline phosphatase (ALP) levels, indicative of enhanced bone turnover. Hypercalcemia persisted despite the cessation of calcium-based phosphate binders, vitamin D supplements, and administration of pamidronate. Management efforts with cinacalcet were hampered by gastrointestinal side effects. Imaging confirmed parathyroid hyperplasia, presenting as nodules with significant technetium-99 uptake. The patient's history included coronary artery disease, bipolar disorder, hypothyroidism, type 2 diabetes, hypertension, and stable asymptomatic multiple myeloma. Further complicating his medical course, he suffered an ST-elevation myocardial infarction in December 2017, necessitating percutaneous coronary intervention, which precluded him from undergoing parathyroidectomy. His immobility, compounded by multiple infections, led to a diagnosis of immobility-induced hypercalcemia along with severe tertiary hyperparathyroidism. Despite treatment, his PTH levels remained elevated, and ionized calcium levels continued to rise, leading to the reintroduction and escalation of cinacalcet. Ultimately, a single dose of denosumab successfully resolved his hypercalcemia and improved symptoms such as energy level and bony pain. However, this resulted in hypocalcemia, necessitating the temporary withholding of cinacalcet, and initiation of calcium carbonate supplementation. Although PTH levels initially peaked post-denosumab, subsequent treatment adjustments achieved a significant reduction in PTH and stabilization of serum calcium. Unfortunately, despite the biochemical improvements, the patient died in July 2018 due to infection-related complications.
Study Author Conclusions	Our case report, which is the first described use of denosumab for treatment of hypercalcemia in the setting of tertiary hyperparathyroidism in a peritoneal dialysis patient, adds to the body of literature suggesting denosumab is a useful therapeutic agent in patients with ESRD. Issues with post-treatment electrolyte management and other therapeutic considerations are also discussed.

References:

Pratt RM, West ML, Tennankore KK. Use of denosumab to treat refractory hypercalcemia in a peritoneal dialysis patient with immobilization and tertiary hyperparathyroidism. Perit Dial Int. 2020;40(1):103-106. doi:10.1177/0896860819880095

Use of high-dose denosumab in the management of immobilization-related hypercalcemia in an end-stage renal disease patient on hemodialysis: A case report and review of the literature
Design	Case report
Case presentation	A 50 kg female patient with a significant medical history, including cerebral infarction from artery thrombosis, end-stage renal disease (ESRD) on hemodialysis, diabetes mellitus, hypertension, recurrent depression, and psychosis, was admitted to the ICU for a suspected hemodialysis catheter-related bloodstream infection and septic shock. Prior medications included calcium carbonate, alfacalcidol, cinacalcet, atorvastatin, nifedipine, pre-mixed insulin, aripiprazole, risperidone, and paroxetine. Upon admission, her hemodialysis catheter was replaced, and blood cultures were performed, showing no bacterial growth. A CT scan revealed bilateral pneumonic patches, leading to treatment with meropenem and colistin after an infectious disease consultation. Despite clinical improvement, the patient required inotropes and developed hypercalcemia, with serum calcium levels rising from 2.52 mmol/L to 3.40 mmol/L. Low-calcium dialysate was unavailable, and medication-induced hypercalcemia was ruled out by discontinuing calcium carbonate and alfacalcidol. Further investigations, including CT scans and serum analysis, did not identify specific causes for hypercalcemia. Treatments with increased cinacalcet dosage, zoledronic acid, and calcitonin initially reduced calcium levels but were not sustained. Denosumab was administered due to insufficient response to previous treatments and side effects from cinacalcet, leading to a rise in calcium levels up to 4.20 mmol/L. Upon re-administration of a higher denosumab dose, calcium levels began to decline. Eventually, calcium levels normalized to 2.45 mmol/L and were maintained for three months without adverse reactions. The patient's bone profile improved, with decreased parathyroid hormone levels, increased vitamin D, decreased serum phosphorus, and decreased alkaline phosphatase over the treatment period. The use of denosumab for managing immobilization-related hypercalcemia in this hemodialysis patient demonstrated its efficacy in long-term calcium regulation.
Study Author Conclusions	We report a case of a hemodialysis patient with immobilization-related hypercalcemia successfully treated with high-dose denosumab.

References:

Zaitoun MF, Al-Alsheikh KA, Elnazer W. Use of high-dose denosumab in the management of immobilization-related hypercalcemia in an end-stage renal disease patient on hemodialysis: A case report and review of the literature. Clin Nephrol. 2021;96(6):353-356. doi:10.5414/CN110058