What Is Hypercalcemia (High Calcium) in Cancer? Causes, Symptoms, and Treatment

Hypercalcemia affects up to 30% of cancer patients. Although it occurs in most cancers, it is particularly common in patients with non–small-cell lung cancer, breast cancer, multiple myeloma, squamous cell carcinoma of the head and neck, urothelial cancer, and ovarian cancer.

Hypercalcemia is a condition in which calcium levels in the bloodstream rise above normal. It generally results from excessive calcium release from bones into the blood, inadequate calcium excretion by the kidneys, or excessive calcium intake through the digestive system. It may be a sign of various diseases and can occur in serious conditions, particularly cancer.

Hypercalcemia in cancer patients can have noncancer causes as well as cancer-related causes.

Its noncancer causes may be similar to those in the general population.

Hypercalcemia Subtypes and Symptoms

Hypercalcemia is defined as a serum calcium concentration more than 2 standard deviations above the mean.

Hypercalcemia can be classified as:

• Mild (10.5-11.9 mg/dL),
• Moderate (12.0-13.9 mg/dL), or
• Hypercalcemic crisis (14.0-16.0 mg/dL).

Cancer-associated hypercalcemia is divided into four subtypes:

• Humoral,
• Local osteolytic,
• 1,25-dihydroxyvitamin D-mediated, and
• Ectopic hyperparathyroidism.

Malignancy-associated (cancer-associated) humoral hypercalcemia occurs when tumor cells produce PTHrP (parathyroid hormone-related protein), a protein resembling parathyroid hormone. It binds specific receptors in bones and kidneys, increasing calcium release from bones into the bloodstream and calcium reabsorption in the kidneys. This raises blood calcium levels.

If cancer has metastasized to the bones, local osteolytic hypercalcemia can occur. In this condition, tumor cells in bone release substances that increase the activity of bone-resorbing osteoclasts and suppress that of bone-forming osteoblasts.

Some tumors can produce parathyroid hormone (PTH), which is normally produced by the parathyroid glands. Ectopic hyperparathyroidism is the name for this condition, in which PTH may cause hypercalcemia by triggering calcium release from bones.

Some tumors alter vitamin D metabolism and thereby raise calcium levels. They overproduce an enzyme that converts vitamin D into its active form, 1,25-dihydroxyvitamin D. Active vitamin D increases calcium absorption from the intestines and calcium release from bones, raising blood calcium levels.

Related topic: What Are Bone Metastases? Why Does Cancer Spread to Bone, and How Is It Treated?

What Are the Symptoms of Hypercalcemia?

Hypercalcemia may cause kidney stones, chronic kidney disease, bone pain, excessive urine output, gastrointestinal problems (nausea, vomiting, constipation), pancreatitis, gastric ulcers, and neuropsychiatric symptoms such as anxiety, depression, weakness, and confusion.

The most common symptoms of cancer-associated hypercalcemia are:

• Fatigue and weakness
• Excessive thirst and urination
• Nausea and vomiting
• Loss of appetite and weight loss
• Constipation
• Abdominal pain
• Changes in mental status, such as confusion or difficulty concentrating
• Muscle weakness
• Bone pain or fractures

Why Is Hypercalcemia Important in Cancer?

Hypercalcemia can be the first sign of some hematological cancers but often goes unrecognized by nononcologists.

Patients may have very vague symptoms and think they are simply tired and thirsty. Sometimes this continues for a long time, and the disease may finally reveal itself through hypercalcemia when they present to the emergency department.

In patients receiving active cancer treatment, hypercalcemia often does not pose a problem because oncologists monitor calcium levels as part of routine laboratory testing.

For patients in remission, whose cancer treatment has ended and who are being followed, unexpectedly high calcium levels may signal cancer recurrence, particularly if they also report fatigue and sleepiness.

Doctors are good at recognizing the symptoms and laboratory findings of hypercalcemia. However, if it is not suspected, this readily manageable condition can easily be overlooked.

How Is Hypercalcemia Tested?

The simplest way to detect hypercalcemia is to measure serum calcium.

Tests to investigate the cause may also include serum PTH, calcitonin, vitamin D, ionized calcium, phosphorus, magnesium, and alkaline phosphatase levels, kidney function, and the urinary calcium-to-creatinine ratio.

What Is Corrected Calcium?

Corrected calcium is a measurement that adjusts total calcium for the albumin concentration in blood plasma. Albumin is a blood protein to which calcium binds; therefore, low albumin levels can make total calcium levels misleading.

Corrected calcium is generally calculated using this formula:

• Measured total calcium + 0.8 x (normal albumin level – measured albumin level)

When albumin is low, this formula more accurately reflects the actual free calcium level.

Identifying the cause of hypercalcemia is important for choosing the best management approach, and its severity may also affect the cancer treatments selected.

Treating Hypercalcemia in Cancer Patients

Hypercalcemia disrupts the kidneys' filtration function and increases urine production, causing dehydration (fluid loss). High calcium can also cause gastrointestinal symptoms, triggering nausea and vomiting that further increase fluid loss.

The main treatments for hypercalcemia include intravenous (IV) fluids to correct dehydration (fluid loss) and treatments that reduce bone resorption, such as bisphosphonates or denosumab . Calcitonin, glucocorticoids, and, in some cases, dialysis may also be used.

Ultimately, the underlying cancer needs to be treated to improve the condition of patients with cancer-associated hypercalcemia.

Recommendations for treating cancer-associated hypercalcemia in adults are as follows:

• Cancer-associated hypercalcemia should be treated with intravenous (IV) bisphosphonates or denosumab. Of these two options, denosumab is preferred over bisphosphonates.
• For severe hypercalcemia with very high calcium levels (serum calcium >14 mg/dL [3.5 mmol/L]), a combination of short-acting calcitonin, which loses its effect within 48-72 hours, and an IV bisphosphonate or denosumab is recommended.
• Denosumab is recommended for patients whose hypercalcemia recurs or does not improve after prior IV bisphosphonate treatment.
• In patients with tumors causing high calcitriol levels who are already receiving corticosteroid drugs, an IV bisphosphonate or denosumab should be added if symptomatic or severe hypercalcemia persists.
• For hypercalcemia due to parathyroid cancer, a calcimimetic is recommended in mildly symptomatic cases, while an IV bisphosphonate or denosumab is recommended for more severe hypercalcemia.
• If hypercalcemia due to parathyroid cancer cannot be controlled with a calcimimetic, an IV bisphosphonate or denosumab may be added.
• For hypercalcemia due to parathyroid cancer that is not controlled with an IV bisphosphonate or denosumab, adding a calcimimetic is appropriate.

Because cancer-associated hypercalcemia is generally linked to advanced disease or aggressive biology, oncologists may need to consider involving palliative care services in some cases. For example, hypercalcemia detected during treatment may mean treatment is not working as well as hoped and that it is time to discuss end-of-life care with the patient.

Summary and Recommendations

Hypercalcemia is common in cancer patients and can have serious consequences without timely, appropriate intervention. Treatment approaches vary with its type and severity. Treating the underlying cause is essential and is generally supported by IV fluids and bone-modifying drugs. Improving quality of life and controlling hypercalcemia are critical to maintaining the effectiveness of oncological treatment and improving overall health. In addition to treating hypercalcemia, oncologists must remain vigilant to identify and prevent this potentially life-threatening condition early. This applies both to patients receiving active cancer treatment and those in remission. Managing hypercalcemia within the complexity of cancer care requires a multidisciplinary approach and encourages patient-centered treatment planning.

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Image descriptions: The article's image was generated with Microsoft Copilot using the prompt: "Could you visualize these terms? Fatigue, thirst, nausea and vomiting, loss of appetite, constipation, abdominal pain"