From the Guidelines
The next steps in managing a patient with hypercalcemia and normal alkaline phosphatase levels should focus on identifying the underlying cause while initiating appropriate treatment with aggressive intravenous fluid rehydration and bisphosphonates, as recommended by the most recent guidelines 1. Initial management includes aggressive intravenous fluid rehydration with normal saline at 200-300 mL/hour to restore intravascular volume and enhance renal calcium excretion. For moderate to severe hypercalcemia (calcium >12 mg/dL), bisphosphonates such as zoledronic acid 4 mg IV or pamidronate 60-90 mg IV should be administered, with a preference for zoledronic acid as stated in the NCCN guidelines 1. Calcitonin 4 IU/kg subcutaneously every 12 hours can provide rapid but temporary calcium reduction. Diagnostic workup should include:
- PTH
- PTHrP
- 25-hydroxyvitamin D
- 1,25-dihydroxyvitamin D
- Serum and urine protein electrophoresis
- Chest imaging to evaluate for primary hyperparathyroidism, malignancy, or granulomatous diseases, as suggested by the clinical guidelines 1. The normal alkaline phosphatase suggests absence of significant bone turnover disorders or metastatic bone disease, narrowing the differential diagnosis. Primary hyperparathyroidism and malignancy-associated hypercalcemia (particularly PTHrP-mediated) are the most likely causes, with the former being potentially curable with parathyroidectomy 1. If primary hyperparathyroidism is confirmed, surgical parathyroidectomy is the definitive treatment. For malignancy-associated hypercalcemia, treating the underlying cancer is essential while maintaining hydration and using bone-modifying agents to control calcium levels, as outlined in the guidelines for managing hypercalcemia in patients with lung cancer 1 and multiple myeloma 1.
From the Research
Next Steps in Managing Hypercalcemia with Normal Alkaline Phosphatase (ALP) Levels
- Identify the underlying cause of hypercalcemia, as treatment depends on the cause 2, 3, 4
- Measure serum intact parathyroid hormone (PTH) to distinguish between PTH-dependent and PTH-independent causes of hypercalcemia 2
- For patients with primary hyperparathyroidism (PHPT), consider parathyroidectomy or observation with monitoring, depending on age, serum calcium level, and kidney or skeletal involvement 2, 5
- For symptomatic or severe hypercalcemia, initial therapy consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate 2, 3
- Consider the use of denosumab in patients with severe hypercalcemia due to PHPT, especially when immediate surgery is not feasible 5
- For hypercalcemia of malignancy, management includes hydration, calcitonin, bisphosphonates, denosumab, and in certain patients, prednisone and cinacalcet 4
- In patients with advanced underlying kidney disease and refractory severe hypercalcemia, consider hemodialysis 4
Diagnostic Considerations
- Obtain fasting total and ionized calcium measurements to confirm hypercalcemia 6
- Use fasting ionized calcium levels for diagnostic purposes, as they are more accurate than total calcium levels 6
- Avoid measuring calcium levels after ingestion of calcium supplements or calcium-containing nutrients, as this can cause transient elevations in blood calcium levels 6