Calcium-Based Disorders

More than 99% of calcium in the human body is found in the skeleton. The remaining calcium is in blood and is maintained at between 8.5–10.5 mg/dL. Nearly half the calcium in blood is bound to either negatively charged proteins or anions, and the remainder is free (ionized) calcium. Control of serum calcium concentration involves the interplay of bone resorption, urinary excretion, and intestinal absorption, which is mediated in part by parathyroid hormone (PTH) and vitamin D.

In this section, we review the presentation, diagnosis, and management of the following calcium-based disorders:

• Hypercalcemia

• Hypocalcemia

Hypercalcemia

Hypercalcemia is defined as a serum calcium level of two standard deviations above the mean of values found in people with normal calcium levels. Hypercalcemia is a common presentation in primary care and the emergency department. Malignancy is the most common cause of hypercalcemia presenting acutely and symptomatically, while primary hyperparathyroidism is the most common cause of chronic or incidentally noted hypercalcemia. Together, they account for more than 90% of cases. Other causes of hypercalcemia are noted in the following figure:

(Source: Case 4-2011 — A 4-Year-Old Boy with Back Pain and Hypercalcemia. N Engl J Med 2011.)

Hypercalcemia of malignancy: Malignancy can cause hypercalcemia through several mechanisms:

• humoral hypercalcemia of malignancy (HHM): caused by systemic secretion of PTH–related protein (PTHrP)

• activation of vitamin D into its active form (1,25-dihydroxyvitamin D [1,25(OH)2D]) by some lymphomas

• receptor activator of nuclear factor kappa-B ligand (RANKL)–associated secretion in acute lymphoblastic leukemia (ALL) and some T-cell lymphomas

• ectopic secretion of authentic PTH (rare)

(Source: Hypercalcemia Associated with Cancer. N Engl J Med 2005.)

Hypercalcemia due to primary hyperparathyroidism: In patients with primary hyperparathyroidism, serum calcium levels are elevated due to elevated PTH levels. In 80% of cases, this is due to a single parathyroid adenoma. The remainder of cases are due to more than one adenoma or hyperplasia of all four glands. Patients with hyperparathyroidism, including mild cases, are at increased risk for renal stones, bone loss, and fractures. Surgery is indicated in symptomatic individuals and in asymptomatic individuals who meet one of the following criteria:

• age <50 years of age

• osteoporosis on dual-energy x-ray absorptiometry (DEXA) scan or based on the presence of a fragility fracture

• renal calculi

• impaired renal function

• hypercalciuria

• blood calcium level ≥1 mg/dL above the upper limit of normal

In patients who meet surgical indications but who decline surgery or cannot undergo surgery due to medical comorbidities, medical management with cinacalcet can be used to correct serum calcium levels but may not be as effective in preventing the adverse effects of primary hyperparathyroidism (such as osteoporosis).

Clinical Features

The following table summarizes signs and symptoms of elevated calcium levels:

Diagnosis

• Most laboratories measure total serum calcium level.

• Serum level of ionized calcium is important to measure in situations (including malignancy) where changes in albumin level can affect total serum calcium level.

• PTH level should be measured to help differentiate between PTH-related causes of hypercalcemia (including malignancy and primary hyperparathyroidism) and non-PTH-related causes (including sarcoidosis and milk-alkali syndrome).

• Phosphorous and vitamin D (at least 25-hydroxyvitamin D) levels should be measured; plasma 1,25(OH)2D level can also be considered and should be measured if granulomatous disorders or the 1,25(OH)2D lymphoma syndrome are included in the differential diagnosis.

Management

Treatment for hypercalcemia is aimed at lowering serum calcium by inhibiting bone resorption, increasing urinary calcium excretion, or decreasing intestinal calcium absorption. Use of the following treatment options will depend on the cause and severity of hypercalcemia:

• aggressive intravenous (IV) volume repletion: usually at a rate of 200–500 mL/hr but depends on the patient’s volume state; target urine output of approximately 2 mL/kg/hr

• loop diuretics (furosemide): only after the patient is adequately volume repleted, to allow continued volume expansion without causing volume overload

• IV bisphosphonates (zoledronic acid or pamidronate, adjusted for presence of renal dysfunction): should be administered immediately because they can take as long as 2 days to start working

• denosumab: a human monoclonal antibody against RANKL that inhibits the maturation, function, and survival of osteoclasts

• other medications:

  • glucocorticoids: reserved for hypercalcemia due to granulomatous disease/elevated 1,25(OH)2D levels

  • calcitonin: can be used as a bridge treatment until bisphosphonates start working but can be associated with development of tachyphylaxis after several days of use

• following serum phosphorus levels closely and keeping in range

• discontinuing oral calcium supplements and calcium in enteral feeding

• reviewing medications for drugs (including lithium) that may independently increase calcium levels

• treating underlying condition, including malignancy and granulomatous disease following treatment of acute symptomatic hypercalcemia

• dialysis as last resort

Hypocalcemia

Hypocalcemia is less common than hypercalcemia and can be classified as acute or chronic. Patients with acute hypocalcemia can have symptoms ranging from perioral numbness and muscle cramps to carpopedal spasm, laryngospasm, and focal or generalized seizures. On physical examination, patients may have signs of neuromuscular irritability, which can be elicited with Trousseau sign or Chvostek sign. Severe hypocalcemia can be associated with electrocardiogram (ECG) changes.

Treatment

• for patients with serum calcium levels between 7.5–8.0 mg/dL:

  • oral calcium and vitamin D supplementation

• for patients with serum calcium levels <7.5 mg/dL:

  • IV calcium

  • frequent monitoring of serum calcium

  • repletion of magnesium

Last updated: October 2023