Management of severe hypercalcaemia secondary to primary hyperparathyroidism: The efficacy of saline hydration, furosemide, and zoledronic acid

Abstract Introduction Severe hypercalcaemia is a life‐threatening condition that should be managed urgently. The aim of this study was to assess the efficacy of saline hydration, furosemide, and zoledronic acid in the management of severe hypercalcaemia secondary to primary hyperparathyroidism (PHPT). Methods We conducted a retrospective analysis of the management of 65 patients with severe hypercalcaemia (≥3 mmol/L) secondary to PHPT. The efficacy of each therapeutic agent was evaluated according to the variation in serum calcium level calculated as Δ calcium = initial calcium level – minimal calcium level reached after the administration of each agent. Results The mean age of patients was 56.4 ± 13.8 years. At baseline, the mean total serum calcium level was 3.42 ± 0.40 mmol/L. After normal saline hydration, calcium level decreased from 3.25 ± 0.21 to 2.98 ± 0.2 mmol/L (p < 10−3) in 3.1 ± 1.7 days. Normalization of calcium level did not occur in any patient. Furosemide was prescribed in 35 patients. It resulted in a serum calcium increase of 0.09 ± 0.21 mmol/L. Calcium levels did not reach the normal range in any patient. Forty‐five patients received intravenous zoledronic acid. The mean maximal reduction in serum calcium level was 0.57 ± 0.27 mmol/L (from 3.25 ± 0.26 mmol/L to 2.68 ± 0.22 mmol/L, p‐value <10−3). Normalization of calcium levels occurred in 27 patients (60%). Conclusions Our results show the absence of a significant additional effect of furosemide on calcium levels in patients with severe hypercalcaemia secondary to PHPT when compared with the effect of saline hydration alone. However, zoledronic acid was more potent. Thus, appropriate normal saline hydration with immediate intravenous bisphosphonates infusion should be considered in the management of severe hypercalcaemia in patients with PHPT.


| INTRODUC TI ON
Severe hypercalcaemia in the setting of primary hyperparathyroidism is called hyperparathyroid crisis. Its incidence ranges from 1.6% to 6%. 1,2 Presentations of hyperparathyroid crisis are heterogeneous including neurological alteration, dehydration, hypovolaemia, anorexia, vomiting, cardiac arrhythmia, impaired cardiac, and renal functions, and finally death if the condition is untreated. 3 Thus, the parathyroid crisis should be managed urgently. Parathyroidectomy represents today its only curative treatment option. However, preoperative medical antihypercalcaemic therapy is warranted as a holding measure. It consists of intravenous saline hydration, a loop diuretic, intravenous administration of bisphosphonates, and calcimimetics. Data evaluating the efficacy of these treatments are very limited.
The aim of this study was to assess the efficacy of saline hydration, furosemide, and zoledronic acid in the management of severe hypercalcaemia secondary to primary hyperparathyroidism.

| ME THODS
This was a retrospective, single-centre study including patients with severe hypercalcaemia secondary to primary hyperparathyroidism who were admitted between January 2012 and March 2021.
Inclusion criteria were patients with primary hyperparathyroidism aged more than 18 years, with a corrected total serum calcium level ≥3.5 or ≥3 mmol/L with signs of poor tolerance (confusion, lethargy, coma, dehydration, electrocardiogram changes, acute renal failure, etc.), and who received a symptomatic treatment before surgery.
Non-inclusion criteria were chronic severe renal failure, heart failure, pregnancy, lactation, and other causes of hypercalcaemia. The dose and the duration of each therapeutic agent prescribed (saline hydration, furosemide, and zoledronic acid) were noted in each patient. The infusion rate of saline hydration was adjusted according to the patient's age and comorbidities, hydration status, and serum calcium levels. Furosemide was administrated after proper hydration by saline solution with adequate control and supplementation of electrolytes. Intravenous zoledronic acid was used in patients whose calcium levels remained ≥3 mmol/L, despite appropriate saline hydration alone or with furosemide administration.
The efficacy of each therapeutic agent was evaluated according to the variation in serum calcium level calculated as Δ calcium = calcium level before the administration of each therapy -minimal calcium level after. Normalization of serum calcium was defined by a level of <2.6 mmol/L.

| Statistical analysis
Data were analysed using SPSS (Statistical Package for the Social Sciences) version 24. Categorical variables were presented as percentages and continuous variables as mean ± standard deviations.
The comparisons between quantitative variables were made using Student's t-test and in case of non-validity by the non-parametric Mann-Whitney test. The level of significance was set at 0.05.

| RE SULTS
Sixty-five patients (58 women and 7 men) were enrolled in this study. Their mean age was 56.4 ± 13.8 years [extremes: .
Hypercalcaemia was incidentally discovered in 29% of cases, in the presence of renal, bone, digestive, and cardiac manifestations in 38%, 14%, 5%, and 2% of cases, respectively, and impaired general condition in 12% of patients.
The baseline characteristics of patients are shown in Table 1.
At admission to our department, the mean albumin-corrected serum calcium level was 3.42 ± 0.40 mmol/L with extremes of 3 and Medical treatment modalities and their results are shown in Table 2. Intravenous normal saline hydration was prescribed alone in all patients with an infusion of two to four litres per day for 3.1 ± 1.7 days. Forty-four patients received 3-4 L/24 h and 21 patients received 2 L/24 h. Serum calcium levels decreased in all patients after hydration but did not reach normal levels. The mean Δ calcium was of 0.27 ± 0.14 mmol/L (extremes: 0.025-0.62 mmol/L).
There was no significant difference between patients who received 2 L/24 h and those who received 3-4 L/24 h.   Figure 3 shows the changes in serum calcium levels in patients receiving zoledronic acid and saline hydration with or without furosemide.    Saline hydration alone is rarely sufficient to reach normal calcium levels in patients with severe hypercalcaemia. It is estimated that with saline hydration, the serum calcium concentration decreases by about 0.4 to 0.6 mmol/L. 8,9 In our study, all patients had a decrease in serum calcium levels with a mean value of 0.27 ± 0.14 mmol/L (extremes: 0.025-0.62 mmol/L) after saline hydration. However, normalization of calcium levels did not occur in any patient.
Once the intravascular volume is restored to normal, loop diuretics can be used in patients with severe hypercalcaemia to obtain a further reduction of calcium levels and to prevent fluid overload. 10 Furosemide is a potent natriuretic that increases calcium excretion by inhibiting calcium reabsorption in the thick ascending limb of the loop of Henle. 8 Before the advent of bisphosphonates, furosemide was an attractive alternative in the management of severe hypercalcaemia. [11][12][13] However, recent data do not support its routine use in the management of severe hypercalcaemia. 14    Abbreviation: n, number of patients.
The difference is statistically significant in bold. (40-60 mg/day, orally) did not achieve normalization at 12 days. 15 Based on these findings, LeGrand et al. 13 concluded that furosemide should be relegated to the management of fluid overload. On the contrary, Robey et al. 16 considered that furosemide remains an important tool in the management of severe hypercalcaemia. Its efficiency depends on adequate attention to volume status and fluid balance before and during furosemide administration. 16 In our study, calcaemia did not reach normal ranges in any patient after furosemide administration but increased in 63% of the cases. The mean increase in calcaemia was 0.09 ± 0.21 mmol/L. Furthermore, the use of diuretics can induce metabolic complications such as hypokalaemia, hypophosphataemia, hypomagnesaemia, hypernatraemia, and metabolic acidosis. 13 Thus, appropriate monitoring and supplementation of these disorders are necessary.

F I G U R E 2
In addition to the general measures, therapeutic agents that act on the main pathophysiological mechanism of hypercalcaemia which is the increased bone resorption should be prescribed in patients with persistent severe hypercalcaemia. 6,7 Bisphosphonates are natural analogs of pyrophosphates that bind to hydroxyapatite and act on osteoclasts by inhibiting their function and reducing their F I G U R E 3 Changes in serum calcium levels in patients receiving zoledronic acid and saline hydration with or without furosemide.

F I G U R E 4
Percentage of patients with normal, decreased, or increased calcium levels after each therapeutic agent. viability. 7,17 Oral bisphosphonates are poorly absorbed, with 1% or less of the administered dose being taken up. 18  Calcimimetics were not used in our patients because they are not available in our country.
Denosumab is a receptor activator of nuclear factor kappa-Β ligand inhibitor that decreases bone resorption. In a study including 10 patients with severe hypercalcaemia secondary to a primary hyperparathyroidism, Eremkina et al. 22 showed that denosumab is a useful tool to reduce calcium level before surgery or if surgery is contraindicated.
Although our study has several limitations, such as its retrospective design and the relatively small number of included patients, it provided a detailed assessment of the impact of hydration, furosemide, and bisphosphonates in the management of severe hypercalcaemia secondary to primary hyperparathyroidism.

FU N D I N G I N FO R M ATI O N
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data used to support the findings of this study are available from the corresponding author upon reasonable request.