Approximately 99% of calcium in the body is bound to bones and teeth. The remaining 1% is found in the serum. Serum calcium exists in an ionized form, a protein-bound form, and a complexed fraction. About half of the total extracellular calcium is ionized, and half is bound mainly to albumin or, to a lesser degree, to other proteins and anions. The ionized form is the biologic component active in the regulation of intracellular and extracellular functions (McDonnell Keenan & Wickham, 2005).

Hypercalcemia occurs when calcium is mobilized from the bone storage areas to the circulation, where it is reflected in total serum calcium values. Serum calcium values are affected by serum protein levels in that every change of total serum albumin of 1 g/dL is associated with a 0.8 mg/dL change in total calcium (Body, 2004). Therefore, because cancer patients frequently have low albumin levels which, in turn, yield falsely low serum calcium measurements, the serum calcium values may need to be corrected for protein concentration to reflect true serum calcium (Table 23-1).

Another strategy in these patients is to obtain an ionized calcium measurement, which more accurately denotes hypercalcemia (values greater than 1.35 mmol/L are considered hypercalcemic), but the test is more expensive and less readily available (McDonnell Keenan & Wickham, 2005). In adults, a total serum calcium level (adjusted for protein concentration) greater than 10.5/dL is considered hypercalcemic (Stewart, 2005; Guise & Mundy, 1998). There is no standard hypercalcemia severity scale, but a calcium level greater than 10.5 mg/dL but less than 12 mg/dL may be classified as mild hypercalcemia. Hypercalcemia is considered severe when the calcium level is above 13.5 to 15 mg/dL (Stewart, 2005; Shuey & Brant, 2004; Davidson, 2001).

Normal calcium homeostasis is maintained by negative feedback loop interactions between parathyroid hormone (PTH), calcitriol, an active metabolite of vitamin D (1,25-dihydroxycholecalciferol), and calcitonin. PTH stimulates osteoclastic bone resorption and the release of calcium and phosphate from bone. It stimulates calcium reabsorption and inhibits phosphate reabsorption from the renal tubules. It also stimulates 1,25-dihydroxycholecalciferol production from the kidney, which plays a role in intestinal calcium and phosphate absorption. Calcitonin directly inhibits osteoclastic bone resorption (Guise & Mundy, 1998).

Normal bone undergoes continual and dynamic remodeling by osteoclasts and osteoblasts, which interact in a balance of bone resorption and rebuilding in response to the normal mechanical stressors placed on the bone. The process is orchestrated by numerous growth factors, hormones, and cytokines (Lipton, 2004).

Four primary biologic pathways have been identified in the development of tumor-induced hypercalcemia (TIH). Each pathway may be solely responsible for TIH, or they may interact with varying degrees of complexity (Guise & Mundy, 1998).

Most commonly (in about 80% to 90% of occurrences), TIH is related to the secretion of parathyroid hormone–related protein (PTHrP) by cancer cells (Stewart, 2005; Saunders et al., 2004; Guise & Mundy, 1998). PTHrP is distinctly different from but behaves in a biologically similar manner to PTH (Guise & Mundy, 1998). PTHrP is increased in the presence of factors such as epidermal growth factor, insulin, IGF-I and IGF-II, TGF alpha and beta, angiotensin II, and the src protooncogene. It is decreased by glucocorticoids and 1,25-dihydroxycholecalciferol (Guise & Mundy, 1998). Although PTHrP has been identified in normal tissue and in normal human physiology, tumor-produced PTHrP interacts with PTH receptors in bone and kidney to cause enhanced renal retention of calcium, osteoclast-mediated bone resorption, and increased phosphate excretion in patients with malignancy (Guise & Mundy, 1998). Tumor-secreted PTHrP has been identified in a variety of solid and hematologic malignancies. About 60% of breast cancers secrete PTHrP which, in addition to being a mediator of hypercalcemia, may also play an important part in the pathophysiology of breast cancer metastasis to bone (Guise & Mundy, 1998).

About 20% of TIHs result from factors that increase osteoclastic bone resorption in areas of the bone infiltrated with malignant cells (Stewart, 2005; Saunders et al., 2004). IL-1, IL-6, TNF alpha, and tumor necrosis factor have been identified as agents with the ability to stimulate osteoclastic resorption, with resultant hypercalcemia. Prostaglandin E may play a minor part in metastatic tumor–related bone resorption and hypercalcemia (Guise & Mundy, 1998).

In fewer than 1% of occurrences, TIH may be related to ectopic production of true PTH (Stewart, 2005). Also, some hematologic malignancies (e.g., lymphomas) secrete 1,25-dihydroxycholecalciferol, thereby enhancing osteoclastic bone resorption and increasing intestinal absorption of calcium (Stewart, 2005; Saunders et al., 2004).

Malignancy has been reported as the most common cause of hypercalcemia in hospitalized patients. It has also been cited as a frequently undiagnosed and undertreated condition (Lamy et al., 2001). TIH is most commonly observed in breast, lung, and hematologic malignancies, but it has been seen with virtually all malignancies, including melanoma and vulvar, renal, ovarian, aerodigestive, and prostate cancers (Bilenchi et al., 2005; Penel et al., 2005; Wu et al., 2004; des Grottes et al., 2001; Lamy et al., 2001; Guise & Mundy, 1998). Classically, TIH has been observed in 10% to 20% of patients with malignancies (Saunders et al., 2004). However, with the use of bisphosphonates in patients with bone involvement of multiple myeloma and breast cancer, the incidence of hypercalcemia has been empirically observed to be decreasing (although this has not fully been documented by evidence) (Maxwell et al., 2003; Body, 2004; McCloskey et al., 2001).

TIH occurs most frequently in patients with advanced malignancies and is considered to be an indicator of a poor prognosis (Penel et al., 2005; Stewart, 2005; Lamy et al., 2001). Treatment of the underlying malignancy is the most important factor in determining the prognosis (Kristensen et al., 1998). In a retrospective study of 84 patients, Siddiqui and colleagues (2002) found that age, presenting symptoms, hemoglobin, platelets, creatinine, and albumin did not predict mortality. Male gender, an underlying diagnosis other than multiple myeloma, and a higher initial serum calcium level at presentation predicted early mortality. Penel and colleagues (2005) found a 72% mortality rate, with a median overall survival of 35 days, in a population of patients with aerodigestive cancers and TIH. Kristensen and coworkers (1998) determined an overall median survival in breast cancer patients of 6.7 months after the first episode of TIH, with higher initial calcium levels being predictive of decreased survival time. Higher calcium levels at presentation may reflect increased severity of the underlying malignancy, which partly explains why successful return to normocalcemia does not seem to improve the prognosis (Kristensen et al., 1998).

The goals of treatment include correction of dehydration, inhibition of bone resorption, an increase in renal excretion of calcium, and treatment of the underlying malignancy. Because antihypercalcemic therapy is considered a palliative therapy that has no ultimate effect on survival (Stewart, 2005), prompt treatment of the malignancy is imperative. However, in cases of advanced, symptomatic malignancy for which no effective cancer treatment is available, a humane approach may be no treatment. Left untreated, patients experience a rapid rise in calcium and resultant unawareness of their condition because of increasing encephalopathy.