Hypercalcemia in association with malignant disease was first reported by Zondek and colleagues in 1924,¹ and the first review of a large series was by Gutman and coworkers in 1936.² Since then the syndrome has become increasingly well recognized and characterized. The frequency with which hypercalcemia occurs varies considerably with tumor type, but it is most commonly seen in association with squamous carcinoma of the bronchus, carcinoma of the breast, and multiple myeloma. It is of considerable interest that some tumors that frequently metastasize to bone—for example, small-cell carcinoma of the lung, carcinoma of the prostate, and some other common tumors, such as adenocarcinoma of the colon and stomach—are infrequently associated with hypercalcemia.

Etiology

Before we discuss the possible etiologies of hypercalcemia in malignant disease, a short review of normal calcium homeostasis is appropriate. (For a more extensive review, see the article by Peacock.³) The adult human body contains approximately 1 kg of calcium, of which all but 10 g is lodged in bone. Most of the extraosseous calcium is found in the extracellular fluid, but the minute concentrations present in cells (10⁻⁸ to 10⁻⁷M) are vital to normal cellular function and control. The total amount of calcium in the body is dependent on the balance between calcium intake and calcium loss. Figure 37-1 demonstrates normal calcium metabolism.⁴ Normal dietary calcium intake is approximately 1 g per day (25 mmol). Absorption of dietary calcium is incomplete (25% to 50%), and in healthy persons it is approximately 300 mg (7.5 mmol per day). Although an enormous reservoir of calcium is present in bone, very little transfer of calcium (on the order of 500 mg or 12.5 mmol per day) occurs between bone and plasma in healthy persons. When net calcium balance is zero, the body is required to excrete approximately 150 mg (3.75 mmol) of calcium daily. The kidney filters large amounts (10 g or 250 mmol) of calcium daily. Of this amount, 65% is reabsorbed in the proximal convoluted tubule, 25% is reabsorbed in the ascending limb of the loop of Henle, and a variable amount is reabsorbed in the distal convoluted tubule. Calcium reabsorption in the proximal tubule is independent of hormonal control but is closely linked to the reabsorption of sodium, a phenomenon that has important consequences in, and implications for, the treatment of hypercalcemia. Calcium reabsorption from the distal tubule is enhanced in the presence of parathyroid hormone (PTH), and it is at this site that the fine-tuning of calcium homeostasis occurs. Bone resorption can increase by approximately 150% over bone formation before the renal clearance mechanisms are overwhelmed.

Figure 37-1 Normal calcium homeostasis. *Ca,* Calcium; *ECF,* extracellular fluid. (From Mundy GR. Calcium homeostasis: hypercalcemia and hypocalcemia. London: Martin Dunitz; 1990. Reprinted with permission.)

The total plasma calcium consists of free plasma calcium (which amounts to approximately 50% of the total) and calcium bound to albumin (and to a lesser extent to other proteins, including paraproteins), which varies with the level of plasma proteins but accounts for approximately 40% of the total. The remaining 10% is in complex with ions such as bicarbonate and citrate (Fig. 37-2). In physiological terms, the plasma free (or “ionized”) calcium carries the greatest significance. Direct measurement of the plasma free calcium is possible using ion-selective electrodes, but for the most part, total plasma calcium is measured. A reasonable correlation exists between serum albumin and serum calcium levels, and therefore algorithms have been suggested to “correct” the total plasma calcium for albumin concentration. Although no algorithm is 100% specific or sensitive for the detection of all true cases of hypercalcemia, the following equation has the merits of accuracy and simplicity.

Figure 37-2 The constituents of total calcium within the serum.

< ?xml:namespace prefix = "mml" />Ca(corrected)=Ca(measured)+(0.8×[4−albumin concentration])

Conventional units

Ca(corrected)=Ca(measured)+(0.02×(40−albumin concentration])

SI units

The serum level of ionized calcium is tightly controlled. The major hormonal determinant of ionized calcium is PTH. This hormone brings about its effects by altering calcium resorption from bone, calcium reabsorption in the kidney, and, via stimulation of formation of active vitamin D (1,25-(OH)₂D₃), calcium absorption from the gastrointestinal tract. The active form of circulating PTH is a polypeptide containing 84 amino acid residues; however, only the first 34 amino acid residues are required for activity related to calcium homeostasis. Several larger C-terminal fragments of PTH are found in circulation (most notably in the presence of renal insufficiency). The role of these peptides, and particularly the large PTH(7–84) fragment (which has been postulated to have antagonistic properties to PTH(1–84) and is secreted from the parathyroid glands during hypercalcemia), remains controversial. An excellent review on the topic of PTH has been written by Potts.⁵

PTH release and, to a lesser extent, formation is under the control of the calcium-sensing receptor (CaSR), which is located on the external cell membrane of parathyroid chief cells. This receptor is a G-protein coupled receptor with a large extracellular domain that is responsible for calcium binding, seven transmembrane domains, and a smaller intracellular domain responsible for signal transduction. Stimulation of the CaSR by even mild changes in ionized calcium level results in a rapid and profound change in the secretion of PTH, as well as more delayed effects on PTH formation.⁶

The parathyroid glands also manufacture the hormone calcitonin. Although pharmacologic doses of calcitonin have effects on plasma calcium levels when given acutely, considerable controversy remains about its true physiological role ⁷ because in both the absence of calcitonin (after a total thyroidectomy) and in the presence of large circulating amounts (seen in medullary carcinoma of the thyroid), gross disturbance of calcium balance is extremely rare.

An understanding of normal calcium homeostasis makes it clear that three potential mechanisms can cause hypercalcemia of malignancy. Calcium can be mobilized from bone in quantities sufficient to overwhelm the renal excretory mechanism, renal reabsorption of calcium can be inappropriately increased (or excretion can be decreased), and gastrointestinal absorption of calcium can be enhanced.

Types of Hypercalcemia of Malignancy

Humoral Hypercalcemia of Malignancy

In 1980, Stewart and colleagues ⁸ described a series of 50 patients with hypercalcemia and malignant disease. In their extensive metabolic evaluation, they were able to characterize the patients into two groups dependent on their excretion of nephrogenous cyclic adenosine monophosphate (cAMP). Patients with high nephrogenous cAMP shared other features with primary hyperparathyroidism, including a lowered renal phosphate threshold. However, significant differences between these groups were found in terms of fasting urinary calcium excretion, 1,25-(OH)₂D₃ concentrations, and immunoreactive PTH levels. The investigators concluded that urinary nephrogenous cAMP was a useful marker for identifying hypercalcemia of malignancy associated with a humoral factor—so-called humoral hypercalcemia of malignancy (HHM)—but that this factor was not native PTH.

Parathyroid Hormone–Related Protein

Advances in molecular biology, in association with the failure to detect circulating immunoreactive PTH in patients with hypercalcemia, cast increasing doubt on the role of native PTH in HHM. In 1983, Simpson and colleagues,⁹ using complementary DNA probes to PTH messenger RNA (mRNA), failed to demonstrate the production of PTH mRNA in many of the tumors considered to be prime candidates for ectopic PTH secretion.

In 1987, Burtis and associates,¹⁰ Moseley and coworkers,¹¹ and Strewler and colleagues¹² published descriptions of a polypeptide hormone isolated from tumors that are associated with the hypercalcemia of malignancy. The primary structure of these peptides shows considerable N-terminal homology with native PTH (Fig. 37-3) and has led to the terminology “parathyroid hormone–related protein” (PTHrP). Although PTHrP is the main humoral factor in patients with hypercalcemia of malignancy, information is increasing about its normal physiological roles.¹³ Furthermore, the importance of PTHrP is increasingly being recognized, not only in the genesis of HHM, but also in the facilitation of cancer growth and metastasis and interaction with the RANK/RANK-ligand/osteoprotegerin system.¹⁴

Figure 37-3 Sequence homology between parathyroid hormone–related protein (*PTHrP*) (1–34) and parathyroid hormone (*PTH*) (1–34). Blue circles indicate identical amino acids between the polypeptides; purple and yellow circles indicate that the corresponding amino acids are not identical.

The identification of the cytokine system involving RANKL, the target of this polypeptide (receptor activator of nuclear factor-κB [RANK]), and the controlling inhibitor osteoprotegerin (OPG) that acts as a soluble decoy receptor has represented a major breakthrough in the understanding of local control of bone cell biology (reviewed by Hofbauer and Heufelder ²⁰). Essentially, RANKL, which normally is produced by osteoblasts, is responsible for osteoclast differentiation and function. In patients with multiple myeloma, the RANK/RANKL/OPG system is deranged. Multiple myeloma cells in the bone marrow increase the presence of RANKL either by direct secretion or by stimulating stromal cell production. Furthermore, depression of OPG availability occurs, both at the level of protein synthesis and after OPG has been secreted as a result of binding to CD-138 (syndecan-1) elaborated by multiple myeloma cells.²¹

The picture of hypercalcemia in persons with multiple myeloma is further complicated by the various renal defects that are a feature of at least 20% of patients with this condition. The major impact is a reduction in glomerular filtration rate, which decreases the ability of the kidneys to excrete a calcium load.

Carcinoma of the Breast

Hypercalcemia is generally considered to be uncommon in patients with carcinoma of the breast in the absence of widespread osseous metastases. Bony destruction is again mediated by stimulated osteoclasts. It has been suggested that breast cancer cells themselves might be capable of resorbing bone, but this does not seem to be a major mechanism. Breast cancer cells are able to produce or induce a number of factors in the local bone microenvironment that could act at a local level to enhance osteolysis (including transforming growth factor–α, IL-8, IL-11, and prostaglandins—particularly of the E series).

Despite this finding, it is also clear that not all cases of hypercalcemia in persons with carcinoma of the breast are wholly dependent on metastatic disease. Indeed, one of the original tumor types from which PTHrP was isolated was breast cancer.¹⁰ In an early study of 98 women with varying degrees of breast cancer, Bundred and coworkers²² noted elevated PTHrP levels in 12 of 13 hypercalcemic patients. Furthermore, tumor staining for PTHrP was positive in 22 of 25 patients who had bone metastases and in whom hypercalcemia later developed.

It has become increasingly clear that cell-cell interaction between breast cancer cells and local bone cells has much to do with the maintenance of the metastatic phenotype in bone. Local production of PTHrP by breast cancer cells can increase osteoclast development and recruitment via RANKL. Enhanced bone resorption can release stored factors, including insulin-like growth factor–1 and transforming growth factor–β. These substances support the growth of the malignant cells. Osteoclastic mobilization of calcium increases tumor production of PTHrP (mediated in part by the CaSR), resulting in a vicious cycle. Cellular cross talk as it relates to bone metastases has been elegantly reviewed by Yoneda and Hiraga.²³

Special Cases

Pseudohypercalcemia

The phenomenon of pseudohypercalcemia is a rare condition in which excess calcium bound to nonalbumin plasma proteins results in an elevated total serum calcium concentration. These proteins are usually monoclonal proteins associated with multiple myeloma and benign monoclonal gammopathy.²⁴ The ionized calcium concentration is normal under these circumstances, but correction formulas using albumin give falsely abnormal results.

Multiple Endocrine Neoplasia

The multiple endocrine neoplasia (MEN) syndromes are a group of disorders associated with hyperfunction of two or more endocrine glands. Hyperparathyroidism or parathyroid hyperplasia is a feature of both MEN-1 and MEN-2. Hypercalcemia is usually mild and frequently asymptomatic. The role of parathyroidectomy is unclear in persons with MEN-1 and MEN-2B, but the association with medullary carcinoma of the thyroid in persons with MEN-2A means that it will more frequently be undertaken in this condition. The fact that the hyperplastic parathyroid glands display the CaSR renders them susceptible to treatment using calcimimetics (discussed later in this chapter).

Tamoxifen-Linked Hypercalcemia

Hypercalcemia in association with the use of estrogen or antiestrogen therapy for carcinoma of the breast has been recognized for more than 50 years. The severity of the hypercalcemia is variable, but it can be fatal. The mechanism by which tamoxifen and similar agents cause hypercalcemia is unclear. Cell culture studies suggest that prostaglandins could be the main mediators of the response.²⁵ A role for prostaglandins would be compatible with the clinical picture of a tamoxifen “flare,” which, in addition to the hypercalcemia, is frequently associated with bone pain.

Evaluation of the Patient

That malignancy is the cause of hypercalcemia is usually not difficult to establish. Nonetheless, careful consideration of other causes of hypercalcemia is warranted for all patients. The differential diagnosis of isolated hypercalcemia is a long one (Table 37-1). It is worth noting, however, that immobilization is common in patients with cancer, that primary hyperparathyroidism is not a rare disease, and that the iatrogenic causes of hypercalcemia are easily remedied. An excellent review of rarer causes of hypercalcemia has been written by Jacobs and Bilezikian.²⁶

Table 37-1

Causes of Hypercalcemia (Other Than Malignant Disease)

Type	Cause
Endocrine	Hyperparathyroidism
	Hyperthyroidism
	Addison disease
Iatrogenic	Immobilization
	Vitamins A and D
	Thiazide diuretics
	Lithium
Other	Paget disease of bone
	Granulomatous disease

Clinical Findings

The syndrome of hypercalcemia of malignancy is often overlooked because many of the symptoms are nonspecific or vague and are ascribed to the underlying malignant process or to its therapy. The symptoms of hypercalcemia are protean. Only parts of the old dictum of “stones, bones, abdominal groans, and psychic moans” used in the description of the symptoms due to primary hyperparathyroidism hold true.

Gastrointestinal symptoms are present in nearly all affected individuals. Nausea, anorexia, and vomiting are early symptoms, but they can easily be confused with the adverse effects of tumor treatment or with symptoms produced directly by the tumor itself. By inducing dehydration and hence aggravating the hypercalcemia, these complications set up a vicious cycle. Constipation is common, and complete ileus can occur at severely raised calcium levels. Cramping abdominal pains, such as those seen in persons with primary hyperparathyroidism, are encountered occasionally, but acute pancreatitis or peptic ulceration complicating the hypercalcemia of malignancy is extremely rare.

The major effect of hypercalcemia on the kidney is to impair renal concentrating ability. Urine, dilute compared with plasma, is excreted in a large volume. As the hypercalcemia and the polyuria persist, volume depletion ensues, with a resultant decrease in the glomerular filtration rate. Further impairment of the kidney’s ability to handle the abnormal calcium load occurs, and the hypercalcemia is aggravated. Tubular damage continues and manifests as acquired renal tubular acidosis, glycosuria, and aminoaciduria. An important consequence of the tubular malfunction is a natriuresis, which results in a sodium loss that aggravates the hypercalcemia, in that the mechanisms for conserving sodium and calcium within the kidney are similar. A syndrome akin to nephrogenic diabetes insipidus occurs, and polydipsia is therefore an early feature. Unfortunately, the gastrointestinal symptoms of anorexia and vomiting overcome the thirst, and intense dehydration can occur. Nephrocalcinosis and nephrolithiasis require hypercalcemia of a prolonged duration and are therefore atypical of the syndrome.

Neuropsychiatric symptoms of apathy, depression, and fatigue are frequently overlooked and ascribed to the underlying neoplasm. Muscle weakness itself can be profound and can confine the patient to bed. This immobility leads to further calcium mobilization and enhances the hypercalcemia. As hypercalcemia continues to worsen, confusion and finally coma supervene. Focal neurologic symptoms, including ataxia, that resolve upon normalization of the serum calcium also can occur but are rare.

Pruritus is a well-recognized, if infrequent, complication of hypercalcemia, as are various irritating eye symptoms. They appear with less frequency in persons with malignant hypercalcemia than in persons with primary hyperparathyroidism.

Bone pain is a frequent symptom of both malignant disease and hypercalcemia. Clearly, this bone pain might in part be related to the presence of metastases within bone that cause areas of increased intramedullary pressure, ischemia, or microfractures, but the symptom is also present in the absence of demonstrable metastatic disease.

The syndrome of hypercalcemia of malignancy therefore manifests insidiously, with anorexia, fatigue, apathy, and polyuria, but it can progress rapidly to obtundation and death.

Laboratory Investigations

From a practical point of view, a few well-chosen, simple investigations are all that are required to aid in the diagnosis, therapy, and monitoring of patients. From the academic point of view, these and less readily available investigations can enhance the understanding of the hypercalcemic process in any given individual.

A complete blood cell count and estimation of the platelet count are required. Measurements of serum electrolytes, blood urea nitrogen, and creatinine are mandatory. Because of the importance of protein binding on the “free” calcium concentration, serum albumin should always be measured with the serum calcium, and a correction formula (such as the one previously provided) should be used. In asymptomatic patients with hypercalcemia and multiple myeloma, a serum ionized calcium level should be obtained.

Renal function and the response of the serum calcium level to therapy should be monitored daily until the calcium concentration normalizes and weekly thereafter unless circumstances necessitate more frequent investigation.

Biochemical clues to the presence of HHM due to PTHrP include hypophosphatemia, hyperchloremia, and a mild metabolic alkalosis, although these could not be considered diagnostic. Urinary excretion of calcium is high, as is urinary cAMP. The renal phosphate threshold is low, indicating a renal phosphate leak, and significant hypophosphatemia can result after treatment of the hypercalcemia. Assays for PTHrP are increasingly available but have limited clinical application for the initial diagnosis of hypercalcemia of malignancy.

Serum immunoreactive PTH is low or undetectable unless the primary site of malignancy is the parathyroid gland itself or primary hyperparathyroidism coexists. Vitamin D metabolites are also frequently low in most cases of hypercalcemia, even though PTHrP is capable of stimulating renal 1α-hydroxylase. Measures of osteoblastic function, such as alkaline phosphatase and bone γ-carboxyglutamate (gla) protein (osteocalcin), have little to offer in the diagnosis or management of hypercalcemia.

Radiographs and isotope bone scans might be pertinent for prognostication and follow-up but do not help delineate the cause of the hypercalcemia, nor are they useful in predicting the response to therapy.

Electrocardiographic changes are not infrequent in hypercalcemia. Shortening of the corrected QT interval is the most commonly recognized change, but severe bradyarrhythmias may also occur.

Grading the Complication

Although it is possible to grade hypercalcemia according to mild, moderate, and severe categories on the basis of a biochemical value, it is important to note that the development and severity of symptoms do not seem to be strictly related to the serum calcium level. As a general rule, patients with symptoms readily related to hypercalcemia should be treated as severe cases, regardless of the objective degree of elevation of the calcium level. A frequently made but poorly understood observation is that patients with tumor-induced hypercalcemia often have greater symptomatology for any given rise in calcium level compared with patients who have primary hyperparathyroidism. Our approach to the treatment of hypercalcemia of malignancy is based on the following classification of hypercalcemia. It is worth noting that many variables other than the serum calcium level affect the logical choice for therapy.

Mild Hypercalcemia

Patients with mild hypercalcemia are asymptomatic and have a serum calcium level of less than 3.0 mmol/L. The abnormality is frequently detected as part of the routine biochemical workup in patients with tumor types known to be predisposed to hypercalcemia. These persons are therefore usually outpatients. Although urgent management of the hypercalcemia is not indicated, several considerations must be kept in mind. The natural history of tumor-induced hypercalcemia is for the condition to worsen. A reevaluation of the current antineoplastic regimen and response to treatment is warranted, because the development of hypercalcemia might be an early indication of a diminishing response to therapy. The development of any intercurrent insult to the kidneys is likely to precipitate more severe hypercalcemia. Intercurrent insult includes both any situation in which volume depletion could occur and the introduction of nephrotoxic agents, such as nonsteroidal antiinflammatory agents.

Moderate Hypercalcemia

In asymptomatic patients with a serum calcium level of 3.0 to 3.5 mmol/L, the situation is more serious. Although this level of calcium might not be life-threatening, little is required to tip the scales toward a more serious problem.

Severe Hypercalcemia

Symptoms attributable to hypercalcemia should always be treated as an acute medical emergency. Furthermore, patients with a serum calcium concentration (corrected for albumin) greater than 3.5 mmol/L require urgent treatment.

Treatment

The serum calcium concentration can be reduced in almost all patients with tumor-induced hypercalcemia. A variety of antihypercalcemic regimens remain in common use, although the wide therapeutic index and high success rates of bisphosphonates have resulted in their use as first-line management in most cases. Although it has been possible to target osteoclast-mediated bone resorption in a fairly specific way, the same cannot be said for enhanced renal tubular calcium reabsorption or gastrointestinal calcium absorption. The introduction of calcimimetic agents has provided a specific therapy in relationship to parathyroid carcinoma with hypersecretion of PTH.²⁷

Selection of therapy should be geared to a knowledge of the individual tumor type (and hence to the probable mechanism underlying the hypercalcemia) and to the status of the patient’s renal function and bone marrow reserve. Any specific antineoplastic therapy that can be used, be it surgical, radiotherapeutic, or chemotherapeutic, will be a powerful adjuvant to antihypercalcemic therapy. An excellent clinical review has been published by Stewart.²⁸

Ethical Considerations

The first decision is whether to treat this complication. Unless specific antitumor therapy is available, most patients who experience hypercalcemia of malignancy are in the last few weeks of their lives. A review of patients with aerodigestive squamous cancer demonstrated a median survival of 35 days and a 2-year mortality rate of 72%²⁹ (pulmonary cancers were underrepresented in this study at 12% of the total). Similarly, hypercalcemia was predictive of early death in patients presenting with multiple myeloma.³⁰ Thus it can be argued that treatment is not indicated for all cases of hypercalcemia associated with malignancy. For some patients, however, the use of an effective, safe treatment to ameliorate the substantial morbidity of hypercalcemia and to allow patients to return home is clearly warranted.

General Considerations

The best treatment is one directed specifically and effectively at the underlying malignant disease. Early mobilization is a laudable but often unachievable goal in patients with advanced malignant disease. Thiazide diuretics should be avoided because they promote renal tubular calcium reabsorption.

Although dietary restriction of calcium seems intuitively appropriate, gastrointestinal calcium absorption is low in most cases of hypercalcemia associated with malignant disease. A notable exception is among patients whose tumors are associated with a substrate-dependent 1α-hydroxylase, which allows continued production of calcitriol. Patients taking supplemental vitamin D and vitamin A (β-carotene) should be advised of the hypercalcemic effects of these agents.

Extracellular Fluid Volume Expansion

Most patients with hypercalcemia of malignancy have significant depletion of fluid volume (on the order of 5 to 10 L) due to the combined effects of anorexia, vomiting, and nephrogenic diabetes insipidus. In this state, the glomerular filtration rate is reduced, and the response by the proximal convoluted tubule is to increase sodium retention. Concomitantly, proximal tubular resorption of calcium is also increased. The aim of fluid replacement in these circumstances should be to induce a state of mild fluid overload. Restoration of a normal circulating blood volume restores the glomerular filtration rate and increases the fractional excretion of calcium. Further salt loading, on the other hand, induces natriuresis and concomitant calciuresis. Care must be taken to avoid severe congestive cardiac failure in elderly patients or in patients with poor cardiac reserve. Because of the hypoalbuminemia that frequently accompanies advanced malignant disease, dependent edema is to be expected during volume expansion. Care must also be taken to ensure an adequate intake of free water. In the presence of severe hypercalcemia, a resistance to the distal tubular actions of antidiuretic hormone may predispose obtunded patients to significant hypernatremia. After restoration of euvolemia, a maintenance infusion of 3 L/day of 0.9% saline solution will induce continued natriuresis and calciuresis. Patients should be encouraged to drink freely. During such aggressive fluid management, other electrolyte abnormalities are likely to be uncovered or precipitated. Despite impaired renal function, both hypokalemia and hypomagnesemia are frequent findings, and appropriate supplementation could be required.

Although the serum calcium level can be expected to decrease while a patient is following this regimen, restoration of normocalcemia is unlikely. Failure to restore normal fluid balance, however, will greatly detract from the success of subsequent therapeutic measures.

Calciuretic Therapy

Aside from the calciuretic effects of saline overload, two other agents are commonly used to induce renal calcium wasting: furosemide and calcitonin.

Furosemide

Furosemide is a diuretic agent whose main site of action is in the thick ascending limb of the loop of Henle (thus making this agent a loop diuretic), where it completely and reversibly inhibits the Na⁺/K⁺/2Cl⁻ cotransporter. In the euvolemic and volume-expanded state, the fractional excretion of calcium can be increased by as much as 30% by loop diuretics. If a patient is volume depleted, however, enhanced proximal tubular sodium and calcium resorption can obviate this response. Thus the potential exists for loop diuretics to aggravate hypercalcemia if adequate attention is not given to fluid volume status. In the initial report of the effectiveness of this treatment, the regimen involved the administration of doses of furosemide in the region of 100 mg every 2 hours. Therapy this aggressive would require the facilities of an intensive care unit to ensure adequate fluid monitoring. Although substantial reductions in the serum calcium can be achieved, a rationale for the use of this treatment for other than acute situations is lacking, in that the primary cause of the hypercalcemia—increased bone resorption—is not affected. Given the risks of severe electrolyte disturbances and the availability of potent antiresorptive medication, loop diuretics should be reserved primarily for situations of fluid overload rather than using them as antihypercalcemic agents.³¹

Calcitonin

The renal actions of calcitonin are complex. The calciuretic effect seems to be due to inhibition of calcium reabsorption in the distal tubules. This, in turn, is dependent on an adequate delivery of calcium to the distal nephron, a situation that is compromised by the extracellular fluid volume depletion in hypercalcemia. This renal tubular effect is rapid, however, and the administration of calcitonin can be of great value as an adjunct to more potent antiresorptive therapies.

Antiresorptive Therapy

Given that bone resorption is increased in most cases of hypercalcemia of malignancy, the best treatment after that designed to combat the tumor itself is one directed at bone resorption. The osteoclasts represent the final common pathway for bone resorption in both humoral and local osteolytic hypercalcemia. The following agents, which inhibit osteoclast function, not surprisingly provide highly effective antihypercalcemia treatment.

Bisphosphonates

The bisphosphonates are a class of compounds—structural analogs to pyrophosphate—in which the P-O-P bond is replaced by a P-C-P bond stable to enzymatic cleavage. Figure 37-4 shows the structure of some of the available bisphosphonates compared with the structure of pyrophosphate. Pharmacokinetic and pharmacodynamic studies of bisphosphonates indicate that these compounds are absorbed poorly from the gastrointestinal tract after oral administration. Diet has a profound effect on gastrointestinal absorption, reducing the effective bioavailability of the drugs to zero if taken with food.

Although bisphosphonates have a significant physicochemical effect, preventing the formation and dissolution of calcium compounded with phosphate, it has become clear that the major clinical mechanisms of action relate to inhibition of farnesyl pyrophosphate synthase in the case of aminobisphosphonates and incorporation into adenosine triphosphate–containing compounds, resulting in inhibition of cell function in nonaminobisphosphonates. Both mechanisms promote apoptosis in osteoclasts, whereas the aminobisphosphonates also inhibit osteoclast recruitment.³²

Strong data support the use of the intravenous bisphosphonates zoledronic acid (4 mg over 15 minutes), pamidronate (60 to 90 mg over 2 to 4 hours), ibandronate (4 mg over 1 hour), and clodronate (1500 mg over 4 hours) in the management of hypercalcemia of malignancy. Favorable studies have been reported when comparing bisphosphonates with placebo, calcitonin, glucocorticosteroids, and mithramycin (plicamycin; see an extensive review by Ross and colleagues ³³).

In studies comparing bisphosphonates, pamidronate proved superior to etidronate and clodronate.³⁴ A pooled analysis of two studies involving 287 patients demonstrated a significantly better response rate for zoledronic acid (4 mg and 8 mg) compared with pamidronate (90 mg).³⁵ The complete response rate for both zoledronic acid doses (defined as normocalcemia at day 10) was similar (88.4% for patients given 4 mg and 86.7% for patients given 8 mg), whereas the response rate for pamidronate was 69.7%. Although these studies confirmed the superiority of zoledronic acid to pamidronate in the sample population, it should be noted that the response rate to pamidronate was lower than has been reported in previous trials. A comparative study between ibandronate and pamidronate has shown that the former is at least equal to the latter in terms of biochemical response and possibly is associated with a longer time to recurrence of the hypercalcemia.³⁶

The primary mechanism in the generation and maintenance of hypercalcemia in persons with malignant disease is enhanced bone resorption. However, tumors secreting PTHrP also have a significant influence on renal calcium handling that would not be influenced directly by bisphosphonate therapy. In a review of 147 patients with hypercalcemia of malignancy and available measurement of PTHrP, it was found that, although the hypercalcemia responded well to intravenous ibandronate, the renal tubular calcium index changed only slightly, confirming that the majority of the action of the bisphosphonates was to limit enhanced bone resorption. Although patients with the tumor types associated with higher PTHrP (i.e., lung and upper respiratory tract) had the greatest risk of recurrence of their hypercalcemia, this was not statistically associated with PTHrP levels.³⁷

The duration of response to bisphosphonates is difficult to determine and varies considerably among individuals. Elucidation of the duration of response is also compounded by the high mortality in this group of patients as a result of their tumors and by the introduction of specific and effective antineoplastic therapy for patients with cancers such as breast and multiple myeloma. Median time to relapse in the studies comparing zoledronic acid with pamidronate was 30 to 40 days with zoledronic acid and 17 days with pamidronate.³⁵ Unfortunately, it is not possible to predict the length of time that any specific patient will remain normocalcemic.

In general, bisphosphonate therapy is well tolerated. An acute inflammatory reaction (the so-called first-dose effect) with low-grade pyrexia, bone pain, and myalgias is noted in 10% to 30% of patients. The use of rapid intravenous infusions of clodronate and etidronate has been associated with deterioration in renal function in patients with previously diminished renal reserves. Renal dysfunction has been noted with pamidronate (often in the setting of frequent use at doses higher than recommended). The observation of more frequent renal abnormalities in patients receiving 8 mg of zoledronic acid has led to the recommendation that 4 mg be the starting dose. Hypophosphatemia sufficient to require supplementation is seen with effective management of hypercalcemia in the setting of bisphosphonate use. The mechanisms of phosphate imbalance are unclear but may include preexisting nutritional deficiency aggravated by volume expansion, renal phosphate wasting in association with PTHrP activity, and increased native PTH activity as normocalcemia (or even mild hypocalcemia) follows therapy. Osteonecrosis of the jaw has been associated with the use of aminobisphosphonates in the long-term management of skeletal morbidity from cancer and (infrequently) nonmalignant conditions.³⁸ According to our current understanding of the condition, this side effect would be considered rare after a single treatment for hypercalcemia of malignancy. Infrequently, eye findings including uveitis and scleritis have been associated with aminobisphosphonate use. The management of bisphosphonate adverse effects has been the subject of a comprehensive review.³⁹

Gallium Nitrate

Hypocalcemia was noted as an adverse effect of therapy among patients receiving gallium nitrate for the management of lymphoma.⁴⁰ Thereafter, its effectiveness as an antihypercalcemia agent was confirmed by Warrell and associates.⁴¹ The exact mechanism of action of gallium is unknown, although it is clear that urinary calcium excretion is reduced. By implication, bone resorption is reduced, although no histologic changes were noted in explants of fetal long bones exposed to this agent.

Gallium nitrate requires intravenous administration. The best-investigated regimens involve sequential 5-day infusions of 200 mg/m²/day. At this dose, the drug is relatively free of adverse effects, although caution is required if other nephrotoxic agents (e.g., aminoglycosides) are being used. Clinical trials using gallium nitrate have shown a superior response (in terms of normalization of calcium and duration of normocalcemia) when compared with calcitonin, etidronate, and pamidronate. Gallium nitrate is effective in tamoxifen-induced hypercalcemia, and it has also been suggested that it may be more effective in cancers associated with higher levels of PTHrP (see the review in reference 42).

The major drawback with this therapy is the need for 5 days of infusion, compared with the shorter duration of therapy for the bisphosphonates.

Therapy Directed against Humoral Factors

Calcimimetics

Calcimimetics are agonists at, or modulators of, the CaSR. These receptors are abundant on normal parathyroid gland tissue but are also present on malignant parathyroid tissue. A well-documented case report using an allosteric modulator of the CaSR (rendering the receptor more sensitive to the effects of high calcium) showed improved control of hypercalcemia in a patient with parathyroid carcinoma.⁴³ Parathyroid carcinoma is a rare cause of hypercalcemia of malignancy, and it is equally rare for tumors to manufacture ectopic PTH, and thus the clinical impact of calcimimetics in the area of hypercalcemia of malignancy is likely to be limited. Indeed, the effect of pharmacologic modulation of the CaSR in nonparathyroid cancers is unclear but has the potential to be detrimental by increasing the production of PTHrP as described previously.

Humanized Antibodies to PTHrP

In a murine model, antibodies directed against PTHrP were effective in reversing the HHM and improving nutritional status.⁴⁴ No human clinical trials have been reported.

Osteoprotegerin and Denosumab

As described previously, OPG, a soluble receptor belonging to the tumor necrosis factor receptor superfamily, is thought to act as a modulator of osteoclast differentiation and function by acting as an inhibitory (or decoy) receptor for the polypeptide RANKL. OPG has been shown to reverse hypercalcemia induced by several factors, including IL-1, tumor necrosis factor–α, PTH, PTHrP, and 1,25(OH)₂D₃, in a mouse model of HHM.45,46 No human clinical trials in hypercalcemia of malignancy have been reported, although a phase 1 study using an Fc-OPG construct showed potent antiresorptive effects (including hypocalcemia) of this agent in patients with bone metastases related to myeloma or breast cancer.⁴⁷

Denosumab is a human monoclonal antibody directed against RANKL. It has been shown to reduce markers of bone resorption in patients with multiple myeloma and breast cancer who had normal corrected calcium levels and bony metastases. Mild reductions in calcium levels were seen with this agent, but they were transient.⁴⁸ No human data on hypercalcemia of malignancy have been reported.

Potential advantages of these agents include their subcutaneous route of administration and lack of renal adverse effects. Concerns have been raised about the potential for the development of inactivating antibodies with prolonged use. It is unclear whether human trials specific to hypercalcemia of malignancy will occur with these agents.

Other Therapies

The widespread acceptance of bisphosphonates as first-line therapy for the hypercalcemia of malignancy because of their effectiveness, ease of use, and reasonable safety profile has resulted in a dramatic reduction in the use of alternate therapies.

The antitumoral antibiotic mithramycin (plicamycin) has a direct toxic effect on osteoclasts and is effective at restoring normocalcemia in approximately 80% of treated patients. Despite myelotoxicity and exacerbation of renal dysfunction, it remains a useful agent in cases of resistance to bisphosphonates.

Calcitonin has both calciuretic and antiresorptive actions and thus would seem to be an ideal antihypercalcemic agent. The antiresorptive effects of calcitonin are related directly to osteoclast toxicity and possibly to inhibition of new osteoclast recruitment. When used as a single agent, the hypocalcemic effect of calcitonin is modest at best, and resistance to the effects of calcitonin develops rapidly. Calcitonin can be used in combination with more powerful antiresorptive agents. Under these circumstances, a rapid and enhanced hypocalcemic effect has been documented. In cases of life-threatening hypercalcemia, or when neurologic symptoms are a major feature, we recommend the use of 8 Medical Research Council units/kg given intramuscularly every 6 hours for 1 or 2 days in association with an intravenously administered bisphosphonate. This regimen has the advantage of combining the rapid calciuretic effect of calcitonin with the powerful, prolonged antiresorptive effect of the bisphosphonate.⁴⁹

As discussed previously, prostaglandins (notably prostaglandin E₂) have potent bone-resorbing effects in relationship to certain tumor types. Thus it was hoped that a significant subset of patients might be found who would respond to prostaglandin synthesis inhibitors such as indomethacin. Although well-characterized case reports have shown a good response to these agents, in general they are ineffective for the treatment of tumor-induced hypercalcemia.

Glucocorticoids are commonly used in the management of tumor-induced hypercalcemia despite significant evidence that their usefulness is limited. The mechanism of any hypocalcemic effect produced by these agents is unclear. In patients with multiple myeloma and lymphoid malignancies, glucocorticosteroids may form part of the antineoplastic regimen, thus reducing production of those factors responsible for the hypercalcemia. Furthermore, because glucocorticosteroids block absorption of calcium from the gut, they can be expected to be useful for patients with vitamin D–mediated hypercalcemia where gastrointestinal absorption of calcium is enhanced.

Hemodialysis using a dialysate bath free of calcium can be used in the emergency treatment of hypercalcemia and would be particularly useful in the setting of renal insufficiency, which would preclude aggressive fluid expansion.

Long-Term Treatment

For patients for whom no antitumor therapy is available, long-term survival is unusual. By implication, there are few good long-term studies on the management of hypercalcemia, and most results are anecdotal. Individualization of therapy is the rule. Patients should be advised to drink an adequate volume of fluid (2 to 3 L daily) and to maintain their mobility as long as possible. They should be reminded of the symptoms of hypercalcemia and urged to report for treatment early should those symptoms arise. Table 37-2 shows suggested maintenance treatments for the hypercalcemia of malignancy. It is noteworthy that the effectiveness of antihypercalcemia therapy with bisphosphonates seems to wane with repeated treatments.⁵⁰

Table 37-2

Options for Long-term Management of Hypercalcemia of Malignancy

Agent	Dose	Frequency*
Intravenous zoledronic acid	4 mg over 15 min	Every 2-3 wk
Intravenous pamidronate^†	60-90 mg over 2-4 hr	Every 2-3 wk
Oral pamidronate^‡	200-1200 mg	Daily
Oral clodronate^§	3200 mg	Daily
Oral etidronate^¶	20 mg/kg	Daily
Oral phosphate	2-3 g	Daily
Corticosteroids	Variable	Daily
Multiple myeloma
Carcinoma of the breast
NSAIDs	Variable	Daily

NSAIDs, Nonsteroidal antiinflammatory drugs.

^†Dodwell DJ, Howell A, Morton AR, et al. Infusion rate and pharmacokinetics of intravenous pamidronate in the treatment of tumour-induced hypercalcemia. Postgrad Med J 1992;68:434–9.

^‡Thiébaud D, Portmann L, Jaeger PH, et al. Oral versus intravenous AHPrBP (APD) in the treatment of hypercalcemia of malignancy. Bone 1986;7:247–53.

^§Chapuy MC, Meunier PJ, Alexandre CM, Vignon EP. Effects of disodium dichloromethylene diphosphonate on hypercalcemia produced by bone metastases. J Clin Invest 1980;65:1243–7.

^¶Ringenberg QS, Ritch PS. Efficacy of oral administration of disodium etidronate in maintaining normal serum calcium levels in previously hypercalcemic cancer patients. Clin Ther 1987;9:318–25.

Hasling C, Charles P, Mosekilde L. Etidronate disodium in the management of malignancy-related hypercalcemia. Am J Med 1987;82:51–4.

The importance of palliative care cannot be overemphasized in the management of these unfortunate individuals.

A logical therapeutic regimen for the acute management of tumor-induced hypercalcemia is shown in Box 37-1. This regimen represents one approach to this problem. Other equally valid regimens are possible, and individualization of regimens is mandatory for long-term therapy.

Box 37-1 Management of Hypercalcemia of Malignancy

The most effective way to control the hypercalcemia of malignant disease is by therapy aimed at eradicating or reducing the tumor burden. Chemotherapy, radiation therapy, and surgical therapy all have roles to play. In the absence of effective antitumor therapy, the patient’s general condition and immediate prognosis should be used to guide the decision to embark on aggressive antihypercalcemic therapy, active palliation, or both. The introduction of agents with high efficacy and few side effects has broadened the oncologist’s options.

Our practice is to discuss treatment options with the patients and their families, emphasizing that the drugs used to control the hypercalcemia have little or no impact on the progression of the underlying cancer but will help the symptoms of the hypercalcemia. Volume expansion with 0.9% saline solution is begun immediately. The rate is determined by the state of hydration of the individual patient as assessed by the clinician. An infusion of intravenous bisphosphonate (zoledronic acid or pamidronate) is begun at the same time as saline solution volume expansion. In the presence of severe hypercalcemia and neurologic symptomatology, calcitonin, 8 Medical Research Council units/kg intramuscularly every 6 hours is used in conjunction with the bisphosphonate.

Biochemical response is rapid. The serum calcium level can be expected to decrease after 24 hours. Most patients reach a nadir calcium value in 5 to 7 days. We maintain natriuresis by continuing the saline solution infusion until normocalcemia is reached. Volume overload, as shown by an elevation of the jugular venous pressure, the development of a fourth heart sound, pulmonary congestion, or peripheral edema, is treated with furosemide, which has the added benefit of inducing calciuresis. Care is taken to avoid volume depletion during use of the diuretic. Close attention is paid to renal function and electrolyte balance, because hypokalemia, hypomagnesemia, and hypophosphatemia are common sequelae of this treatment approach. Failure to respond to bisphosphonate therapy is a poor prognostic feature, but alternative antiresorptive therapy can be attempted (e.g., gallium nitrate and plicamycin).

In the absence of effective antitumor therapy, hypercalcemia is almost certain to recur if the patient survives long enough. The duration of normocalcemia is variable, and further antihypercalcemic therapy must be individualized. Patients are advised to maintain a high fluid intake (3 L daily). Corrected calcium concentration is determined weekly. We treat patients again with intravenous bisphosphonate therapy when the corrected serum calcium exceeds 2.7 mmol/L and at regular intervals thereafter. Repeat treatment is performed on an outpatient basis when possible. The dose of bisphosphonate is based on the last dose that reversed the hypercalcemia.

Often the malignant process is at such an advanced stage that death occurs within a few weeks of the development of hypercalcemia. As a result, we involve palliative care personnel early in the management of hypercalcemic patients.