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June 2001 Volume 4, Issue 5:
ASK THE EXPERTS
By James R. Berenson, MD
Essentials of Hypercalcemia
06.01.01

Hypercalcemia, an increased amount of calcium in the blood, is a common metabolic disorder that occurs in 20% of myeloma patients at some time during their disease course.

Pathogenesis
In myeloma patients, hypercalcemia is primarily caused by increased bone loss with the leeching out of calcium from the bone into the bloodstream, and to a lesser extent, increased reabsorption of calcium by the kidney. This increased bone loss is due to the enhanced activity of the bone resorbing cells, the osteoclasts. These cells are stimulated by the presence of a number of different specific proteins known as cytokines that are overabundant in the myeloma bone microenvironment. Previous studies suggested the important role of interleukin 1, tumor necrosis factor and interleukin 6 in leading to loss of bone in myeloma patients. Interestingly, these same cytokines also directly and indirectly stimulate growth and accumulation of tumor cells in myeloma patients. Thus, treatments directed at reducing the amounts or functions of these specific proteins should not only reduce skeletal problems but also have an anti-myeloma effect. More recently, two other proteins, macrophage inflammatory protein 1 alpha and the so-called RANKL, have also been identified to play major roles in the development of myeloma bone disease and resulting hypercalcemia. Several new pharmacological inhibitors of the function of these latter two proteins are in early clinical development. 

Clinical Presentation
Hypercalcemia is defined as a serum calcium level above 12.0 mg/dL. Patients with hypercalcemia usually present with a variety of symptoms resulting from the effects of calcium on multiple different organ systems including the kidneys, gastrointestinal tract, musculoskeletal system, heart, and nerves. Symptoms commonly occurring in hypercalcemic patients may include nausea, vomiting, constipation, edema, weakness, and mental confusion. Since these symptoms are rather nonspecific, the diagnosis is often missed and assumed to be related to the effects of the cancer or treatment-related factors. The severity of symptoms depends on the degree of elevation and the rate of rise in serum calcium. Importantly, many hypercalcemia patients with myeloma have other skeletal complications including bone pain, pathologic fractures, spinal cord compression, and impaired mobility.

Treatment
The treatment for hypercalcemia in myeloma patients has changed very little over the past several years. Mild elevation of serum calcium (serum calcium level <12 mg/dL) may be treated by increasing physical activity, restricting salt intake, and increasing oral fluid intake. However, higher levels of moderate (serum calcium level >12-13.5 mg/dL) or severe (serum calcium level >13.5 mg/dL) hypercalcemia require drug therapy.


The best option for treating hypercalcemia in myeloma patients is controlling the cancer itself. While this is effective in many patients, this positive outcome may take many weeks to months to occur, and hypercalcemia must be reversed much more rapidly to avoid severe consequences for the patient. 
Proper treatment of hypercalcemia is very patient specific and is dependent on the presence and degree of symptoms, the severity of hypercalcemia, and the overall status of the patient (i.e. cardiac status, overall quality of life, and refractoriness of the patient to anti-myeloma therapy). Saline diuresis with or without loop diuretics, with more specific calcium-lowering drugs including calcitonin, glucocorticosteroids, plicamycin, gallium nitrate, and the bisphosphonates have all been used successfully to lower calcium levels and have defined roles in the acute management of cancer-related hypercalcemia.


The cornerstone of treatment for hypercalcemia is aggressive hydration with salt-containing solution (normal saline) and, when indicated, use of loop diuretics, such as furosemide, to allow for maintenance of proper volume status as well as enhance excretion of calcium by the kidney. For myeloma patients with kidney problems who cannot tolerate aggressive hydration and diuresis, dialysis may be required to adequately remove the excess calcium.

Drug Therapy
Many patients with hypercalcemia will require additional therapy to adequately reduce the serum calcium level and to prevent rapid return of symptomatic hypercalcemia. Although calcitonin rapidly lowers serum calcium levels, its effects are short lived. It may be useful in life-threatening cases for patients with rapidly rising serum calcium levels. However, these patients will also require concomitant use of an intravenously administered bisphosphonates to effectively reduce the serum calcium with any significant duration of clinical benefit. By the time tachyphylaxis with calcitonin occurs, the bisphosphonates (see below) are exerting their maximal effect. Glucocorti-costeroids may also be useful in myeloma patients with hypercalcemia both by reducing tumor loads and suppressing the amounts and effects of proteins that lead to bone loss.


Although plicamycin was used in the past to treat hypercalcemia in myeloma patients with a rapid onset of action (i.e. 12 hours); its significant toxicities, including liver, kidney, bone marrow, and bleeding, have greatly reduced its use. It may be useful for the small number of patients unresponsive to bisphosphonate therapy. Gallium nitrate is a potent inhibitor of bone resorption and has had efficacy in the setting of hypercalcemia associated with cancer. Unfortunately, this drug also has significant toxicities; especially related to kidney problems. It also requires continuous intravenous administration for five days. With the availability of safer and more convenient drugs such as the bisphosphonates, this drug is now rarely used to treat hypercalcemic patients.

Bisphosphonates
Bisphosphonates are potent inhibitors of bone resorption that preferentially bind to bones that have high rates of bone turnover (i.e. undergoing increased bone resorption or formation). However, the inhibition of bone resorption by these agents extends beyond the direct physical protection of bone from the effects of the cells that lead to bone loss, the osteoclasts, and includes the inhibition of their development and function as well. These drugs are poorly tolerated and absorbed when given by mouth. These agents administered intravenously have become standard of care for the treatment of patients with significant hypercalcemia of malignancy including for patients with multiple myeloma. The current treatment standard for moderate to severe hypercalcemia is pamidronate 90 mg administered intravenously over several hours. Lower doses of pamidronate (30 or 60 mg) have been shown to be inferior for the treatment of hypercalcemia in cancer patients. Most myeloma patients today also receive monthly intravenous pamidronate to reduce skeletal complications from their increased bone loss. Recent laboratory studies suggest that pamidronate may possess both direct and indirect anti-myeloma properties, and some clinical studies suggest a survival benefit for some patients receiving this drug on a chronic basis.

Zoledronic Acid
Zoledronic acid is the most potent bisphosphonate developed to date. Zoledronic acid is nearly 10,000-fold more potent than bisphosphonates such as etidronate. This drug has been used at very small doses for the treatment of hypercalcemia in cancer patients, and doses as low as 0.002 mg/kg normalized calcium levels in some patients and doses >0.02 mg/kg (approx. 1/100th the dose of pamidronate used to normalize calcium) led to normal calcium levels in all patients with a prolonged duration of response. A recently completed published randomized trial compared zoledronic acid (4 mg or 8 mg) to pamidronate (90 mg) in the treatment of 287 patients with hypercalcemia from a variety of cancers including multiple myeloma. The results of this study established the superiority of the third-generation bisphosphonate, zoledronic acid, in reversing hypercalcemia and achieving a longer duration of response with no difference in adverse events. Only approximately 70% of patients who received pamidronate normalized calcium levels compared to nearly 90% of patients who received either dose of zoledronic acid. The potential benefits of zoledronic acid in terms of potency, efficacy, and convenience, have led to the development of clinical trials to determine its efficacy in several other settings related to bone disease. Early clinical trials studying this new agent in patients with bone metastases have demonstrated its marked anti-bone resorptive activity. Results from a recently completed large randomized trial evaluating the efficacy of newer bisphosphonate compared to pamidronate for the prevention of skeletal complications in myeloma patients should be evaluable soon. Several recently completed large randomized trials evaluate the anti-tumor effect of zoledronic acid. It is hoped that the treatment of bone disease and its complications including hypercalcemia may have the additional benefit of providing the patient simultaneously with an anti-myeloma therapy as well.


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