Pathophysiology and management of severe hypercalcemia

The principal pathophysiologic alteration in severe hypercalcemia accompanying hyperparathyroidism and malignancy is enhanced osteoclastic bone resorption. Hypercalcemia impairs renal mechanisms that lead to sodium and calcium excretion; PTH and PTHrP acting on renal tubules enhance further calcium reabsorption. Although rehydration is often necessary as an initial therapy of hypercalcemia, the cornerstone of therapy is to inhibit osteoclastic bone resorption. The bisphosphonates, plicamycin, gallium, and calcitonin all inhibit osteoclastic bone resorption. Calcitonin is the most rapidly acting agent. Toxicities of calcitonin are minimal, yet its therapeutic efficacy is limited by lack of potency and tachyphylaxis. The second-generation bisphosphonates such as pamidronate represent a class of compounds that are extremely effective in inhibiting the metabolic function of the osteoclast. Given in a single infusion, a significant majority of patients will have normalization of corrected serum calcium lasting, on average, 1-2 weeks. Therapeutic benefit will be of greater duration because most patients remain only minimally symptomatic until corrected serum calcium rises above 11.5 mg/dL. Side effects of low-grade fever, hypophosphatemia, hypomagnesemia, and hypocalcemia may occur. Gallium nitrate is a potent inhibitor of bone resorption and may be of increased clinical value when more efficient administration protocols can be developed. Plicamycin, available for two decades, has cumulative toxicities and is less potent than the aminobisphosphonates. Renal insufficiency often accompanies severe hypercalcemia. The nephrotoxicity of gallium nitrate and plicamycin should preclude their use when there is moderate impairment of renal function, and amino bisphosphonates become the treatment of choice in these patients. Although several authors have advocated individualized approaches to the management of hypercalcemia, the potency and duration of action of the aminobisphosphonates make them a reasonable treatment choice for most patients with symptomatic hypercalcemia. Most importantly, the most effective therapy for hypercalcemia is to recognize and treat the underlying disease. Acute primary hyperparathyroidism requires surgery. The effective treatment of hypercalcemia of malignancy allows the introduction of tumor-specific therapy, limits morbidity, and shortens and deintensifies hospitalization. At times, the most appropriate and compassionate decision (particularly in patients with malignancy who have exhausted all therapeutic options and have relentless bone pain) is to withhold therapy for hypercalcemia. Future therapies directed at the osteoclast, such as more potent later-generation bisphosphonates; inhibitors of osteoclast attachments and inhibitors of peptides, which stimulate osteoclastic bone resorption, may permit safe, easily administered, outpatient therapies that will improve the quality of life for hypercalcemic patients.