Hypercalcemia

Overview
An increased level of calcium in the bloodstream is most often a complication of cancer and is referred to as hypercalcemia of malignancy. In its severe form, hypercalcemia may be a life-threatening emergency. Management of hypercalcemia may involve increasing fluid intake, as well as the use of diuretics and bisphosphonate drugs.

What is hypercalcemia?
Hypercalcemia is an increased level of calcium in the bloodstream. This disorder is most commonly caused by malignancy (called hypercalcemia of malignancy) or primary hyperparathyroidism. Other causes of elevated calcium are less common and are usually not considered until it has been determined that neither malignancy nor parathyroid disease is present. Hypercalcemia of malignancy occurs in approximately 10% of patients with advanced cancers. The occurrence of hypercalcemia may rise as high as 40% in some types of cancer, including breast, lung and multiple myeloma.

What causes hypercalcemia?
Hypercalcemia of malignancy has many causes. It may be related to the spread of cancer from its site of origin to bones in the body, a process called metastasis. Cancer cells can spread, or metastasize, through the blood and lymph systems.  A cancer cell may break away from the original location in the body and travel in the circulatory system until it gets lodged in a small capillary network in bone tissue. Cancer may also spread to bone from the adjacent cancer, though this occurs less frequently than spread by the blood stream. Bone metastases result in injury to the bone tissue.

Although bone appears to be the most static of all the tissues in the body, it is actually very dynamic and active. Normal bone is constantly being remodeled, or broken down and rebuilt. Every week humans recycle 5% to 7% of their bone mass. As much as half a gram of calcium may enter or leave the adult skeleton each day.

One important function of bone remodeling is maintenance of blood calcium levels. Calcium is necessary for many processes in the body, including contraction of muscles, nerve function, blood clotting and cell division. Only 1% of the calcium in the body is available in circulation for these functions. The other 99% is locked in the bones. If blood calcium levels drop, calcium must be released from the bones through remodeling in order to maintain important physiological functions that require calcium.

In the case of hypercalcemia, bone metastases cause an imbalance between bone formation and bone resorption resulting in the release of excess calcium into the blood.

What are the signs and symptoms of hypercalcemia?
Signs and symptoms of hypercalcemia may include:

  • Nausea
  • Fatigue
  • Vomiting
  • Lethargy
  • Stomach pain
  • Moodiness
  • Constipation
  • Irritability
  • Anorexia
  • Confusion
  • Excessive thirst
  • Extreme muscle weakness
  • Dry mouth or throat
  • Irregular heart beat
  • Frequent urination
  • Coma

These many signs and symptoms are commonly attributed to either the cancer treatment or the malignancy itself and may make it difficult for doctors to detect hypercalcemia of malignancy when it first occurs. This disorder can be severe and difficult to manage. Severe hypercalcemia is a medical emergency requiring immediate treatment.

How is hypercalcemia diagnosed?
Hypercalcemia may be diagnosed with a blood test. Blood calcium levels are tested by taking a small amount of blood from the patient with a needle. The blood is collected in tubes and sent to a lab for evaluation.

Normal blood calcium ranges from 8.5 to 10.5 milligrams per decliliter (mg/dL) of blood. The normal range may vary slightly from lab to lab. More than one test may be necessary to determine that blood calcium levels are abnormally high. In a person with cancer, a high blood calcium level is considered a medical emergency and treatment should be started immediately.

How is hypercalcemia treated?
The best treatment for hypercalcemia due to cancer is treatment of the cancer itself. However, since hypercalcemia often occurs in patients whose cancer is advanced or has not responded to treatment, management of hypercalcemia is sometimes necessary.

Treatment for hypercalcemia is based on a number of factors, including the condition of the patient and the severity of the hypercalcemia. Increasing fluid intake and the use of diuretics has been standard practice. Most recently, bisphosphonate drugs have become an effective approach.

Hydration: One of the primary treatments for hypercalcemia of malignancy is hydration, which may consist of increasing oral fluid intake or intravenous (through a vein) administration of fluids. Hydration helps decrease the calcium level through dilution and causes the body to eliminate excess calcium through the urine. For mild-to-moderate elevations of calcium, patients are usually directed to increase oral fluid intake. For acute hypercalcemia, hydration with saline is immediately administered intravenously. The rate of hydration is based upon the severity of the hypercalcemia, the severity of dehydration and the ability of the patient to tolerate rehydration.

Diuretics: Sometimes, hypercalcemia of malignancy is treated with a diuretic. The most commonly used diuretic, furosemide (Lasix®), causes the kidneys to produce more urine. As a result, the amount of free water in the body is reduced. Along with an increase in urine volume, furosemide causes loss of calcium, sodium and potassium. Furosemide is well tolerated; however, it is not free of side effects, which may include dehydration, low blood potassium and low blood sodium.

Furosemide is available by intravenous administration as well as oral tablets. Intravenous method of administration is used to achieve an urgent effect. Oral tablets are used for maintenance. Oral tablets of furosemide are administered once or twice a day.

Bisphosphonate drugs: Recently, bisphosphonates have become effective treatments for preventing the complications of bone metastases including fractures, relieving bone pain and hypercalcemia. The goal of treatment for bone metastases is palliative, to relieve pain and risk of fracture, and has historically consisted of surgery, radiation therapy and pain medications. Bisphosphonate drugs, a newer approach to treatment for bone metastases, can effectively prevent loss of bone that occurs from metastatic lesions, reduce the risk of fractures and decrease pain.

Bisphosphonate drugs inhibit bone resorption, or break-down. Bone is constantly being “remodeled” by two types of cells: osteoclasts, which break down bone, and osteoblasts, which rebuild bone. Although the exact process by which bisphosphonates work is not completely understood, it is thought that bisphosphonates inhibit osteoclasts and induce apoptosis (cell death) in these cells. There is also evidence that these drugs bind to bone, thereby blocking osteoclastic resorption.

Cancer cells release various factors that stimulate osteoclastic activity, causing increased breakdown of bone. By inhibiting osteoclasts, bisphosphonate drugs effectively reduce the detrimental impact that cancer cells have on bone density. Clinical trials have demonstrated the activity of two new bisphosphonate drugs in cancer patients: zoledronic acid (Zometa®) and pamidronate (Aredia®).

Bisphosphonates effectively prevent or delay bone destruction and related pain. This activity has been demonstrated in clinical trials with multiple myeloma1 and breast cancer2 patients. When comparing treatment with chemotherapy plus pamidronate to chemotherapy alone, patients receiving pamidronate were less likely to experience complications related to cancerous involvement of the bone such as fractures. Additionally, patients receiving pamidronate lived longer, had a lesser need for radiation and surgical treatment, and experienced significantly less pain than those patients not receiving the bisphosphonate.

Zoledronic acid demonstrates the strongest activity of these two bisphosphonate drugs. In a recent clinical trial, zoledronic acid was shown to be a safe and effective treatment in prostate cancer patients with bone metastases. Compared to placebo, zoledronic acid significantly reduced the proportion of patients who experienced skeletal complications, extended the time to first skeletal complication, and significantly reduced the risk of skeletal complications over the course of this 15-month study.3 These results are notable because they show activity of zoledronic acid in blastic lesions, in which extra bone has built up, whereas previous trials have only shown activity of bisphosphonates on metastases in which the bone is weakened.

Both zoledronic acid and pamidronate are administered intravenously, but zoledronic acid provides a more convenient regimen for patients. Zoledronic acid is administered in a dose ten times lower than pamidronate, resulting in an infusion time that is significantly shorter: 15 minutes versus 2-4 hours for pamidronate. In an effort to eliminate the need for intravenous administration, research is aimed at developing more effective oral bisphosphonates.

References


1 JR Berenson, A Lichtenstein, L Porter, MA Dimopoulos, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. Journal of Clinical Oncology 1998;16:593-602.

2 Lipton A, Theriault RL, Hortobagyi GN, Simeone J, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases. Cancer 2000:88:1082-1090.

3 Saad F. Treatment of bone complications in advanced prostate cancer: rationale for bisphosphonate use and results of a phase III trial with zoledronic acid. Semin Oncol 2002;29:19-27.