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 persons with cancer. Solid tumors (such as lung or breast cancer) as well as certain hematologic malignancies (particularly multiple myeloma) are most frequently associated with hypercalcemia.[1] 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. It should be emphasized, however, that diagnosis and timely interventions are not only lifesaving in the short term, but also may enhance the patient’s compliance with primary and supportive treatments and may improve quality of life.[2] 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 family who have expressed their wishes regarding end-of-life issues, this may represent a preferred timing and/or mode of death (as compared to 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.

Calcium homeostasis is maintained by 2 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.

Normal, healthy kidneys are capable of filtering large amounts of calcium that is subsequently reclaimed by tubular reabsorption. The kidneys are capable of increasing calcium excretion nearly 5-fold to maintain homeostatic serum calcium concentrations. However, hypercalcemia may occur 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 (see the Mechanisms of Cancer-associated Hypercalcemia section) 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 circulating volume contraction exacerbate dehydration.[3] 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).

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.[4]

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 and humoral hypercalcemia. Osteolytic hypercalcemia is due to direct bone destruction by primary or metastatic tumor. Humoral hypercalcemia is mediated by circulating factors secreted by malignant cells without evidence of bony disease.[5,6] It is now believed that hypercalcemia is due to the release of factors by malignant cells that ultimately cause calcium reabsorption from bone.[1]

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.[6-8] Increased blood levels of PTHrP have been found in patients with solid tumors, but not in patients with hematologic malignancies who develop hypercalcemia.[1]

Circulating growth factors may also mediate hypercalcemia. Potential mediators include transforming growth factor (TGF) alpha and beta, interleukin-1, tumor necrosis factors (TNF) alpha and beta, and interleukin-6.[9]

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.[10]

Hematologic malignancies may stimulate osteoclastic bone resorption through the production of cytokines such as TNF (alpha and beta) and interleukins 1 and 6, formerly referred to as osteoclast-activating factor(s).[4,6,11]

References

1. 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. 
   
   
2. Theriault RL: Hypercalcemia of malignancy: pathophysiology and implications for treatment. Oncology (Huntingt) 7 (1): 47-50; discussion 52-5, 1993.  [PUBMED Abstract]
   
   
3. Mundy GR, Ibbotson KJ, D'Souza SM, et al.: The hypercalcemia of cancer. Clinical implications and pathogenic mechanisms. N Engl J Med 310 (26): 1718-27, 1984.  [PUBMED Abstract]
   
   
4. Mundy GR: Pathophysiology of cancer-associated hypercalcemia. Semin Oncol 17 (2 Suppl 5): 10-5, 1990.  [PUBMED Abstract]
   
   
5. Mundy GR, Martin TJ: The hypercalcemia of malignancy: pathogenesis and management. Metabolism 31 (12): 1247-77, 1982.  [PUBMED Abstract]
   
   
6. Broadus AE, Mangin M, Ikeda K, et al.: Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. N Engl J Med 319 (9): 556-63, 1988.  [PUBMED Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. Dodwell DJ: Malignant bone resorption: cellular and biochemical mechanisms. Ann Oncol 3 (4): 257-67, 1992.  [PUBMED Abstract]
   
   
10. Coleman RE: Bisphosphonate treatment of bone metastases and hypercalcemia of malignancy. Oncology (Huntingt) 5 (8): 55-60; discussion 60-2, 65, 1991.  [PUBMED Abstract]
    
    
11. Warrell RP Jr: Etiology and current management of cancer-related hypercalcemia. Oncology (Huntingt) 6 (10): 37-43; discussion 43, 47-50, 1992.  [PUBMED Abstract]
    
    

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