What is the treatment for severe hypercalcemia?

Comment by InpharmD Researcher

Evidence guiding the optimal treatment strategy for severe hypercalcemia is limited, as most literature focuses specifically on hypercalcemia of malignancy. Current guidance for severe disease (serum calcium >14 mg/dL) suggests initial management with aggressive IV isotonic saline hydration followed by antiresorptive therapy, using an IV bisphosphonate (zoledronic acid preferred) or denosumab, with or without short-term calcitonin. Calcitonin may provide rapid but transient calcium reduction, while antiresorptive agents are the mainstay for sustained control, and glucocorticoids may be used as adjunctive therapy in select etiologies or refractory cases. Treatment should be individualized based on severity, renal function, and underlying etiology.

"severe hypercalcemia"; severe hypercalcemia NOT malignancy; treatment, guidelines

Background

The 2023 Endocrine Society clinical practice guidelines on the treatment of hypercalcemia in malignancy (HCM) define severe HCM as serum calcium (SCa) >14 mg/dL (3.5 mmol/L). For these patients, it is suggested using a combination of calcitonin and an intravenous (IV) bisphosphonate or denosumab as initial treatment, rather than using an IV bisphosphonate or denosumab alone. This recommendation is based on a retrospective study involving 140 patients treated with a bisphosphonate and/or calcitonin for moderate to severe HCM (see Table 1; corrected SCa >13 mg/dL or ionized calcium >1.5 mmol/L). Additionally, the guidelines provide an alternative definition of hypercalcemia severity from the National Cancer Institute's Common Terminology Criteria for Adverse Events. [1]

A 2022 review addressed the management of severe cancer-associated hypercalcemia, defined by corrected calcium levels >13 mg/dL, rapid rises in calcium, or neurologic symptoms. The authors emphasized aggressive intravenous isotonic saline hydration as initial therapy to correct volume depletion and promote calciuresis, followed by antiresorptive therapy as the cornerstone of treatment. Intravenous zoledronic acid was identified as the preferred agent, normalizing calcium levels in most patients within 48-72 hours, while calcitonin was recommended as a short-term adjunct for rapid but transient calcium reduction. Denosumab was supported as an effective alternative in patients with renal impairment or bisphosphonate-refractory disease, with glucocorticoids and dialysis reserved for select etiologies or life-threatening cases. The authors concluded that prompt hydration, early antiresorptive therapy, and treatment of the underlying malignancy are essential for sustained control of severe hypercalcemia. [2]

Severe hypercalcemia is defined as 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). Treatment should be prompt, involving isotonic saline (200-300 mL/h) with IV bisphosphonates with or without calcitonin (depending on renal function). Intravenous zoledronic acid 5 mg over 15 min should be started soon after hydration initiation; slower infusion rates (over 30-60 min) or lower doses of zoledronic acid or denosumab (not renally cleared) may be considered if serum creatinine is elevated. Glucocorticoids may be used as initial adjunctive therapy in patients with known or suspected vitamin D-related hypercalcemia; steroids can also be used adjunctively in refractory life-threatening hypercalcemia of any cause. The therapy approach should be modified based on clinical factors and etiology; hydration alone may be sufficient in certain cases with a known readily-reversable etiology (i.e., milk-alkali syndrome). See Table 2 for specific options. [3]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question: