How to manage a patient with hypercalcemia and normal parathyroid hormone (PTH) levels?

From the Guidelines

Management of hypercalcemia with normal parathyroid hormone (PTH) levels requires identifying and treating the underlying cause while addressing the elevated calcium levels. Initial management includes aggressive intravenous fluid rehydration with normal saline at 200-300 mL/hour to promote calcium excretion, followed by loop diuretics like furosemide 20-40 mg IV after adequate hydration to enhance calcium elimination. For moderate to severe hypercalcemia (>12 mg/dL), bisphosphonates such as zoledronic acid 4 mg IV or pamidronate 60-90 mg IV are effective, with onset within 2-3 days 1. Calcitonin 4 IU/kg SC every 12 hours can provide rapid but temporary relief. Common non-parathyroid causes to investigate include malignancy (particularly with PTHrP production), vitamin D toxicity, granulomatous diseases like sarcoidosis, medications (thiazides, lithium), immobilization, and hyperthyroidism. Laboratory evaluation should include PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, serum and urine protein electrophoresis, and appropriate imaging based on suspected etiology. Long-term management depends on treating the underlying condition, with regular monitoring of serum calcium, renal function, and electrolytes during treatment. Some key points to consider in the management of hypercalcemia with normal PTH levels include:

• The importance of aggressive fluid rehydration and loop diuretics in the initial management of hypercalcemia 1
• The effectiveness of bisphosphonates in reducing calcium levels in moderate to severe hypercalcemia 1
• The need to investigate and treat underlying non-parathyroid causes of hypercalcemia, such as malignancy and vitamin D toxicity 1
• The importance of regular monitoring of serum calcium, renal function, and electrolytes during treatment 1

From the FDA Drug Label

Hypercalcemia of Malignancy Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in metastatic bone disease and hypercalcemia of malignancy Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate.

Patients who have hypercalcemia of malignancy can generally be divided into two groups, according to the pathophysiologic mechanism involved In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid-hormone-related protein, which are elaborated by the tumor and circulate systemically.

Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present.

Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations Therefore, adjustment of the total serum calcium value for differences in albumin levels is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation

The patient has elevated calcium and normal ionized and PTH levels. The FDA drug label does not provide information on how to manage a patient with hypercalcemia and normal PTH levels.

• Key points:
  • The labels discuss hypercalcemia of malignancy.
  • They do not address the specific scenario of elevated calcium with normal ionized and PTH levels.
  • Management of hypercalcemia is generally focused on the underlying cause, which in this case is not clearly identified. The FDA drug label does not answer the question.

From the Research

Hypercalcemia Management

• Hypercalcemia is defined as a serum calcium concentration >10.5 mg/dL, and it is classified into mild, moderate, and severe, depending on calcium values 2.
• The initial approach to managing hypercalcemia involves identifying the underlying cause, which can be primary hyperparathyroidism, malignancy, or other conditions such as granulomatous disease, endocrinopathies, or genetic disorders 3.
• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, as it distinguishes PTH-dependent from PTH-independent causes 3.

Normal PTH and Ionized Calcium Levels

• In some cases, patients may have elevated total calcium levels with normal PTH and ionized calcium levels, which can be seen in patients with normal-function kidney transplant recipients 4.
• Another possible explanation for normal ionized calcium levels despite elevated total calcium is the presence of certain serum proteins, such as IgA paraprotein, which can bind to calcium and reduce the amount of free calcium in solution 5.

Treatment Options

• Mild hypercalcemia usually does not require acute intervention, but symptomatic or severe hypercalcemia requires initial therapy with hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate 3, 2.
• In patients with preexisting renal dysfunction, intravenous bisphosphonates can be used, but with caution, as they may increase the risk of serum creatinine elevations 6.
• Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption, such as in vitamin D intoxication or granulomatous disorders 3.