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.