Overview
Normal Calcium Homeostasis
Hormonal influences
Renal function
Bone resorption
Mechanisms of Cancer-associated Hypercalcemia
Potentiating Factors
Hypercalcemia is the most common life-threatening metabolic disorder associated
with neoplastic diseases, occurring in an estimated 10% to 20% of all adults
with cancer. It also occurs in children with cancer, but with much less frequency (approximately 0.5%–1%).[1-3] Solid tumors (such as lung or breast cancer tumors) as well as certain
hematologic malignancies (particularly multiple myeloma) are most frequently
associated with hypercalcemia.[4] Although early diagnosis followed by
hydration and treatment with agents that decrease serum calcium concentrations
(hypocalcemic drugs) can produce symptomatic improvements within a few days,
diagnosis may be complicated because symptoms may be insidious at onset and can
be confused with those of many malignant and nonmalignant diseases. However, diagnosis and timely interventions not only
are lifesaving in the short term but also may enhance the patient’s compliance
with primary and supportive treatments and may improve quality of life.[5]
When a patient has a refractory, widely disseminated malignancy for which
specific therapy is no longer being pursued, the patient may want to consider
withholding therapy for hypercalcemia. For patients or families who have
expressed their wishes regarding end-of-life issues, this may represent a
preferred timing and/or mode of death (as compared with a more prolonged death
from advancing metastatic disease). This option is best considered long before
the onset of severe hypercalcemia or other metabolic abnormalities that impair
cognition, so that the patient may be involved in the decision making.
Normal Calcium Homeostasis
Hormonal influences
Calcium homeostasis is maintained by two hormones, parathormone (parathyroid
hormone or PTH) and calcitriol (1,25-dihydroxy vitamin D). Minute-to-minute
regulation of serum-ionized calcium is regulated by PTH. PTH secretion is
stimulated when ambient serum-ionized calcium is decreased. PTH acts on
peripheral target cell receptors, increasing the efficiency of renal tubular
calcium reabsorption. In addition, PTH enhances calcium resorption from
mineralized bone and stimulates conversion of vitamin D to its active form,
calcitriol, which subsequently increases intestinal absorption of calcium and
phosphorus. Pharmacologic doses of calcitonin act as an antagonist to PTH,
lowering serum calcium and phosphorus and inhibiting bone reabsorption.
Renal function
Normal, healthy kidneys are capable of filtering large amounts of calcium, which
is subsequently reclaimed by tubular reabsorption. The kidneys are capable of
increasing calcium excretion nearly fivefold to maintain homeostatic serum
calcium concentrations. Hypercalcemia may occur, however, when the
concentration of calcium present in the extracellular fluid overwhelms the
kidneys’ compensatory mechanisms.
Although calcium reabsorption is linked to sodium and fluid reabsorption in the
proximal renal tubules, fine regulation occurs in the distal renal tubules
primarily under the influence of PTH. Tumors that are capable of producing a
substance similar to normal PTH such as PTH-related peptide (refer to the Mechanisms of
Cancer-associated Hypercalcemia section of this summary) drive the renal tubules to increase
calcium reabsorption. Under these circumstances, hypercalcemia and high
calcium concentrations in urine (hypercalciuria) impair sodium and water
reabsorption, causing polyuria (a calcium diuresis) with subsequent loss of
circulating fluid volume (dehydration). As a consequence of dehydration, renal
blood flow and the glomerular filtration rate decrease and proximal tubular
calcium and sodium reabsorption increase, leading to further increases in serum
calcium concentrations. Anorexia, nausea, and vomiting associated with
loss of circulating fluid volume exacerbate dehydration.[6] Immobilization
caused by weakness and lethargy may exacerbate calcium resorption from bone.
The kidneys may be irreversibly compromised if the concentration of calcium in
the glomerular filtrate exceeds its solubility, resulting in calcium
precipitation in the renal tubules (nephrocalcinosis).
Bone resorption
In healthy adults before midlife, bone formation and resorption are in dynamic
balance primarily through the activity of osteoblasts (bone-forming cells) and
osteoclasts (bone-reabsorbing cells). Even though 99% of total body calcium is
contained in bone, bone seems to have a minor function in the daily maintenance
of plasma calcium levels. The normal daily exchange between bone and
extracellular fluid is quite small.[7]
Mechanisms of Cancer-associated Hypercalcemia
The fundamental cause of cancer-induced hypercalcemia is increased bone
resorption with calcium mobilization into the extracellular fluid and,
secondarily, inadequate renal calcium clearance. Two types of cancer-induced
hypercalcemia have been described: osteolytic hypercalcemia and humoral hypercalcemia.
Osteolytic hypercalcemia results from direct bone destruction by primary or
metastatic tumor. Humoral hypercalcemia is mediated by circulating factors
secreted by malignant cells without evidence of bony disease.[8,9] It is believed that hypercalcemia results from the release of factors by malignant cells
that ultimately cause calcium reabsorption from bone.[4]
One such factor is a PTH-like protein known as parathyroid hormone–related
protein or peptide (PTHrP). PTHrP is a primitive protein that appears to have
important roles in calcium transport and developmental biology. It shares
partial amino acid sequence and conformational homology with normal PTH; binds
with the same receptors on skeletal and renal target tissues; and affects
calcium and phosphate homeostasis, as does PTH.[9-11] Increased blood levels of
PTHrP have been found in patients with solid tumors but not in patients with
hematologic malignancies who develop hypercalcemia.[4]
Circulating growth factors may also mediate hypercalcemia. Potential mediators
include transforming growth factor-alpha and -beta, interleukin-1 and -6, and tumor
necrosis factor (TNF)-alpha and -beta.[12]
Potentiating Factors
Immobility is associated with an increase in resorption of calcium from bone.
Dehydration, anorexia, nausea, and vomiting that exacerbate dehydration reduce
renal calcium excretion.
Hormonal therapy (estrogens, antiestrogens, androgens, and progestins) may
precipitate hypercalcemia. Thiazide diuretics increase renal calcium
reabsorption and may precipitate or exacerbate hypercalcemia.[13]
Hematologic malignancies may stimulate osteoclastic bone resorption through the
production of cytokines such as TNF-alpha and -beta and interleukin-1 and -6,
formerly referred to as osteoclast-activating factor(s).[7,9,14]
References
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Leblanc A, Caillaud JM, Hartmann O, et al.: Hypercalcemia preferentially occurs in unusual forms of childhood non-Hodgkin's lymphoma, rhabdomyosarcoma, and Wilms' tumor. A study of 11 cases. Cancer 54 (10): 2132-6, 1984.
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Kerdudo C, Aerts I, Fattet S, et al.: Hypercalcemia and childhood cancer: a 7-year experience. J Pediatr Hematol Oncol 27 (1): 23-7, 2005.
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Warrell RP Jr: Metabolic emergencies. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997, pp 2486-93.
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Horiuchi N, Caulfield MP, Fisher JE, et al.: Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro. Science 238 (4833): 1566-8, 1987.
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Suva LJ, Winslow GA, Wettenhall RE, et al.: A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 237 (4817): 893-6, 1987.
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Dodwell DJ: Malignant bone resorption: cellular and biochemical mechanisms. Ann Oncol 3 (4): 257-67, 1992.
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Coleman RE: Bisphosphonate treatment of bone metastases and hypercalcemia of malignancy. Oncology (Huntingt) 5 (8): 55-60; discussion 60-2, 65, 1991.
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