From the Guidelines
Hypercalcemia should be managed with intravenous normal saline at 200-300 mL/hour to promote calcium excretion, followed by loop diuretics like furosemide 20-40 mg IV once adequate hydration is achieved, and bisphosphonates such as zoledronic acid 4 mg IV or pamidronate 60-90 mg IV for malignancy-related cases, as recommended by guidelines 1. The treatment approach for hypercalcemia depends on the severity and underlying cause of the condition.
- For mild hypercalcemia, increasing fluid intake and addressing the underlying cause may be sufficient.
- For moderate to severe cases, intravenous hydration with normal saline is crucial to correct dehydration and enhance renal excretion of calcium.
- Loop diuretics, such as furosemide, can be added after adequate hydration to further increase calcium excretion 1.
- Bisphosphonates, including zoledronic acid and pamidronate, are effective in reducing calcium levels in patients with malignancy-related hypercalcemia, with a duration of action lasting 2-4 weeks 1. Key considerations in the management of hypercalcemia include:
- Correcting dehydration and promoting calcium excretion through intravenous hydration and loop diuretics.
- Using bisphosphonates for malignancy-related hypercalcemia.
- Monitoring serum calcium levels and adjusting treatment as necessary. Hypercalcemia can occur due to various causes, including primary hyperparathyroidism, malignancy, and medication effects, with symptoms ranging from mild, such as fatigue and constipation, to severe, including cardiac arrhythmias and coma, emphasizing the need for prompt and effective treatment 1.
From the FDA Drug Label
The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of zoledronic acid injection are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease.
Zoledronic acid is used to treat hypercalcemia of malignancy by inhibiting bone resorption. The drug works by:
- Inhibiting osteoclastic activity
- Inducing osteoclast apoptosis
- Blocking osteoclastic resorption of mineralized bone and cartilage
- Inhibiting increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors The treatment of hypercalcemia of malignancy with zoledronic acid is based on its ability to decrease serum calcium and phosphorus levels and increase urinary calcium and phosphorus excretion 2.
From the Research
Definition and Prevalence of Hypercalcemia
- Hypercalcemia affects approximately 1% of the worldwide population 3
- It is defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L) for mild cases, and total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) for severe cases 3
Causes of Hypercalcemia
- Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy 3
- Other causes include granulomatous disease, endocrinopathies, immobilization, genetic disorders, and certain medications or supplements 3
- Less common causes include sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, accounting for less than 1% of cases 3
Diagnosis and Evaluation
- Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, distinguishing PTH-dependent from PTH-independent causes 3
- An elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level indicates another cause 3
Treatment and Management
- Mild hypercalcemia usually does not require acute intervention, but may be managed with observation or parathyroidectomy depending on the underlying cause and patient factors 3
- Symptomatic or severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate 3, 4
- Denosumab may be used as a bridge to surgery in patients with severe hypercalcemia due to PHPT, or in patients with bisphosphonate-resistant hypercalcemia 5, 6
- Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption 3