Endocrinology Metabolism

Tumor induced hypercalcemia

Are You Sure the Patient Has Malignancy-Associated Hypercalcemia (MAHC)?

Symptoms and signs

The development of symptoms depends on the degree and duration of hypercalcemia. Age, comorbidities, rate of rise, and concurrent medication use affect presenting symptoms. Generally people with serum calcium levels above 13 mg/dL [3.25 mmol/L] are symptomatic, though some patients with a very gradual rise in serum calcium levels may remain asymptomatic even with calcium levels above 15 mg/dL [3.75 mmol/L]. Conversely, acute mild hypercalcemia in the 11.0 to 11.5 mg/dL [2.75 to 2.88 mmol/L] range may also cause symptoms, for example in an elderly patient who is taking sedative medications.

  • Neurologic: Hypercalcemia causes cells to become refractory to stimulation due to hyperpolarization of cell membranes. This can lead to a wide range of neuropsychiatric symptoms, from fatigue and confusion to coma. Older patients and those with pre-existing neurologic dysfunction or sedative medications are more likely to experience obtundation, whereas younger patients may remain alert despite moderate to severe hypercalcemia.

  • Renal: Hypercalcemia can prevent normal reabsorption of water in the renal tubule, causing a form of nephrogenic diabetes insipidus. Symptoms include polyuria and increased thirst. The resulting volume depletion combined with hypercalcemia-induced afferent arteriolar vasoconstriction cause reductions in the glomerular filtration rate. Hypercalcemia may also lead to precipitation of calcium phosphate salts in the kidney (nephrocalcinosis) or as nephrolithiasis with or without obstructive uropathy.

  • Gastrointestinal: Smooth muscle involvement may lead to constipation and ileus. Anorexia, nausea, vomiting and abdominal pain are also common. Hypercalcemia may also lead to pancreatitis.

  • Muscular:Hypercalcemia can cause muscle cells to become refractory to neuronal activation, resulting in skeletal muscle weakness.

  • Cardiovascular: Hypercalcemia may lead to abnormalities on electrocardiogram, the most specific of which is shortening of the QTc interval. Vascular calcification is also possible with chronic hypercalcemia.

  • Ocular: Band keratopathy is a rare finding in patients with hypercalcemia. It is visible as a horizontal band across the cornea on slit-lamp examination. Subepithelial calcium phosphate is believed to precipitate in the cornea because of the higher local pH induced by the diffusion of carbon dioxide out of the cornea.

Key Laboratory Findings

Hypercalcemia is defined as a serum calcium above the upper limit of the normal range (generally above 10.6 mg/dl [2.65 mmol/L] for total calcium, or 1.25 mmol/L for ionized calcium). Though there is no formal grading system for severity of hypercalcemia, in general, serum calcium concentrations below 12 mg/dl can be considered mild, those between 12 and 14 mg/dl moderate, and those above 14 mg/dl severe.

Of the total normal total serum calcium concentration of 9.5 mg/dl [2.38 mmol/L], approximately 45% is the physiologically active ionized serum calcium, 10% is complexed to anions, and 40% is bound to serum proteins, principally albumin.

In the case of abnormal albumin levels, the following formula may be used to “correct” the total serum calcium:

  • adjusted total calcium level = measured total calcium level in mg/dL + [0.8 x (4.0 – measured serum albumin in g/dL)]

Thus, a patient with a low albumin level of 2 and a measured total calcium level of 10.2 mg/dL may in fact be significantly hypercalcemic, with an adjusted total calcium level of 11.8 mg/dL. This formula is reasonably reliable, but if questions arise, ionized serum calcium should be directly measured.

What Else Could the Patient Have?

Causes of Malignancy-Associated Hypercalcemia

The most common cause of hypercalcemia among hospitalized patients is cancer. In most cases, the tumors associated with hypercalcemia are large in size; small neuroendocrine tumors such as islet cell tumors are the exception. Malignancy-associated hypercalcemia is a poor prognostic indicator; about half of patients with cancer who are found to have hypercalcemia die within 30 days of detection of hypercalcemia.

  1. Humoral hypercalcemia of malignancy (HHM) causes approximately 80% of hypercalcemia associated with cancer. Hypercalcemia in HHM occurs due to systemic secretion of parathyroid hormone-related protein (PTHrP) by a malignant tumor. PTHrP increases bone resorption and limits renal clearance of calcium, resulting in hypercalcemia. Tumors that most commonly cause HHM are squamous cell carcinoma of any origin, breast, renal carcinomas, ovarian or endometrial carcinomas, though virtually any tumor can cause HHM. In general HHM occurs in the presence of few or no skeletal metastases. If tumor resection or ablation is possible, it may reverse hypercalcemia due to HHM. HHM is also associated with a reduction in the renal phosphorus threshold, which results in phosphaturia and hypophosphatemia.

  2. Local osteolytic hypercalcemia (LOH) causes about 20% of hypercalcemia associated with cancer, though the incidence may be decreasing with the widespread use of bisphosphonates. Hypercalcemia in LOH results from release of cytokines within the marrow space that recruit and activate osteoclasts. The resulting increase in osteoclastic bone resorption in areas surrounding the malignant cells within the marrow space exceeds the ability of the kidney to clear calcium. Tumor burden is generally large in these patients, and the tumor is often a breast cancer or hematologic malignancy such as multiple myeloma, lymphoma, or leukemia.

  3. 1,25 (OH) 2 vitamin D-secreting lymphomas or dysgerminomas cause less than 1% of hypercalcemia associated with cancer. In this syndrome, tumors cause increased production of the active form of vitamin D, synthesized by the 1-alpha-hydroxylase enzyme within the tumor cells. This results in hypercalcemia through increased intestinal absorption of calcium and enhanced osteoclastic bone resorption.

  4. Ectopic secretion of authentic parathyroid hormone (PTH) from other malignant tumors can occur, but is a very rare cause of hypercalcemia.

Other causes of hypercalcemia

Patients with cancer may have hypercalcemia due to a treatable cause, so an evaluation for other etiologies is advised. This is particularly true in patients with cancers that are not commonly associated with hypercalcemia, such as colon, prostate, and gastric carcinomas.

  • Primary and tertiary hyperparathyroidism. Over-secretion of PTH from abnormal parathyroid glands is the most common cause of hypercalcemia among healthy outpatients, who are usually asymptomatic. A patient can have coexisting primary hyperparathyroidism and tumor-induced hypercalcemia. Parathyroidectomy provides definitive treatment.

  • Parathyroid carcinoma is a rare cause of hyperparathyroidism. Patients with parathyroid carcinomas are more likely than those with parathyroid adenomas to have symptoms, a neck mass, bone and kidney disease, marked hypercalcemia and an extremely elevated serum parathyroid hormone (PTH) level.

  • Familial Hypocalciuric Hypercalcemia (FHH) is a benign, autosomal dominant disorder in which inactivating mutations in the calcium receptor cause inappropriate renal conservation of calcium and hypercalcemia with high-normal or mildly elevated PTH. No specific therapy is indicated.

  • Granulomatous disorderscan cause hypercalcemia due to increased activation of vitamin D to 1,25 (OH) 2D by macrophages and giant cells in the granulomas. This stimulates enhanced intestinal absorption of calcium, and to a lesser extent, osteoclastic bone resorption. Hypercalcemia occurs in 10% of patients with sarcoidosis, which is the most extensively studied granulomatous cause of hypercalcemia. Another common cause is tuberculosis, although any granulomatous disease can cause this syndrome.

  • Several endocrine disorders other than hyperparathyroidism are associated with hypercalcemia. These include hyperthyroidism, which causes generally mild hypercalcemia in up to 50% of affected patients. Pheochromocytoma may be associated with primary hyperparathyroidism in multiple endocrine neoplasia type 2, but in other cases removal of the pheochromocytoma itself is enough to correct hypercalcemia. Addisonian crisis may also cause mild hypercalcemia with responds to treatment with fluids and glucocorticoids. Islet cell or other neuroendocrine tumors that produce vasoactive intestinal polypeptide can cause a syndrome in which patients have watery diarrhea, hypokalemia, achlorhydria, and often hypercalcemia.

  • Medications which can result in hypercalcemia include:

    • Thiazide diuretics, which often cause mild hypercalcemia due to increases renal tubular calcium reabsorption.

    • Aminophylline and theophylline, which have been reported to cause mild, transient hypercalcemia through unknown mechanisms when used in supra-therapeutic doses.

    • Lithium, which causes hypercalcemia in up to 5% of patients. It seems to induce PTH secretion and also increases renal tubular calcium reabsorption. Discontinuing lithium and substituting another psychiatric medication often reverses the hypercalcemia; however, this may be impossible due to the underlying bipolar disorder. If hypercalcemia is mild, observation may be a reasonable strategy. If PTH is consistently elevated and hypercalcemia is significant, parathyroidectomy may be considered.

    • Vitamin D stimulates intestinal calcium absorption and osteoclastic bone resorption. In addition to overdose of calcitriol or over the counter vitamin D supplements, Vitamin D intoxication has been reported in cases of excess addition of vitamin D to milk, infant formula or over the counter supplements.

    • Vitamin A (including retinoic acid derivatives) stimulates bone resorption.

    • Foscarnet causes hypercalcemia through unknown mechanisms.

    • Estrogen and tamoxifen may cause hypercalcemia in patients with breast cancer and extensive bone metastases

    • Growth hormone treatment has been reported to cause hypercalcemia in subjects with severe burns and also in subjects with HIV/AIDS. The mechanisms are not known.

    • Teriparatide, used for the treatment of osteoporosis, is associated with hypercalcemia in a substantial minority of patients. In general, the hypercalcemia is mild and requires no treatment or a reduction in the dose of teriparatide or supplemental calcium, though severe hypercalcemia warrants discontinuation of teriparatide therapy.

    • 8-chloro-cyclic AMP, usedas an anti-cancer agent, has been associated with hypercalcemia, possibly through a 1,25(OH) 2 vitamin D-dependent mechanism.

  • Milk-alkali syndrome is a syndrome of hypercalcemia, metabolic alkalosis, hypercalciuria and renal failure which occurs usually occurs in patients consuming large quantities (typically at least 4000 mg elemental calcium per day) of absorbable calcium containing-antacids, such as calcium carbonate. Hypercalcemia occurs as a result of passive intestinal calcium absorption exceeding the ability of the kidney to clear the calcium. The hypercalcemia is reversible with hydration and reduction of calcium intake, though the resulting renal damage may be permanent.

  • Immobilizationcauses hypercalcemia after several weeks in patients with background high bone turnover, such as children or young adults, or adult patients with mild primary or secondary hyperparathyroidism, Paget’s disease, myeloma, or breast cancer with bone metastases. The immobilization activates osteoclastic bone resorption and suppresses osteoblastic bone resorption, leading to loss of calcium from the skeleton, hypercalcemia and reduced bone mineral density. The syndrome is associated with hypercalciuria as well, and this, together with chronic urinary catheterization, leads to urinary tract infection and severe calcium nephrolithiasis. Restoring active weight bearing is the most effective treatment, if possible, though bisphosphonates and hydration are an alternative therapy.

  • Renal failure is a risk factor for hypercalcemia. In patients with chronic renal failure, hypercalcemia may occur as a result of calcitriol treatment, use of phosphate-binding agents, excessive calcium intake from supplements or diet, or immobilization. Hypercalcemia in patients with chronic renal failure may also result from tertiary hyperparathyroidism. Transient rebound hypercalcemia has been described during the resolution phase of acute renal failure due to rhabdomyolysis as serum phosphate concentrations decline.

  • Chronic total parenteral nutrition (TPN) in patients with short bowel syndrome has been associated with hypercalcemia. This is sometimes related to large amounts of calcium, vitamin D or aluminum in the TPN solution, but in other cases, the mechanism is unexplained. High calcium from parenteral or enteral feeding combined with reduced calcium clearance due to renal insufficiency can also cause hypercalcemia similar to milk-alkali syndrome.

  • Factitious hypercalcemia may occur in patients with elevated levels of serum albuminor in rare cases of calcium-binding immunoglobulins in multiple myeloma or Waldenstrom's macroglobulinemia. In these cases, the amount of calcium bound to proteins may be elevated though ionized calcium will be normal. Patients display an elevation in total serum calcium without symptoms or signs of hypercalcemia or evidence of hypercalciuria. Since ionized calcium levels are normal, these patients do not require treatment of hypercalcemia. Medications to lower calcium can result in hypocalcemic seizures despite normal measured total calcium.

  • End-stage liver disease has been noted to cause hypercalcemia which reverses with successful liver transplant. The underlying mechanism is unknown.

  • Manganese intoxication in patients who drink water from contaminated wells has been described as a cause of hypercalcemia.

  • Severe dietary phosphate restriction in animals causes hypophosphatemia associated with hypercalcemia. Although this has not been documented in humans, hypophosphatemia is often associated with hypercalcemia in cancer, hyperparathyroidism, and other causes of hypercalcemia. Anecdotally, treatment of hypercalcemia may be more successful once hypophosphatemia is corrected.

Key Laboratory and Imaging Tests

Key Laboratory Tests

  • Total serum calcium: As mentioned above, the total serum calcium concentration is comprised of ionized serum calcium and serum calcium bound to proteins, mainly albumin, and anions, such as phosphate, sulfate, carbonate or citrate. Ionized calcium is the only physiologically active form, but it is not routinely measured. The total calcium level should be adjusted for albumin levels as described above. Hypercalcemia is present when the adjusted total calcium level is greater than two standard deviations above the normal mean in a particular laboratory (often 10.6 mg/dL [2.65 mmol/L])

  • Albumin:Since albumin is the main protein to which calcium is bound, a person with hypoalbuminemia may have hypercalcemia despite measured calcium in the normal range. Using an albumin level, an adjusted calcium level can be calculated and compared to the total calcium reference range. If significant abnormalities in the level of bound calcium are expected, an ionized calcium may be a more precise reflection of biologically active calcium.

  • Ionized calcium: Ionized calcium is the physiologically active form of calcium. Since estimates of adjusted total calcium are not always reliable, measurement of ionized calcium should be considered if abnormalities in the level of bound calcium are expected. An ionized calcium greater than two standard deviations above a laboratory’s normal mean (often 1.4 mmol/L) reflects hypercalcemia. Calcium-binding immunoglobulins in rare cases of multiple myeloma may cause misleading elevated total serum calcium levels with a normal ionized calcium level.

  • Phosphorus: Calcium and phosphorus metabolism are closely related. Serum phosphorus may be elevated in vitamin-D mediated hypercalcemia and renal failure and tends to be low in hyperparathyroidism and HHM. Patients with hypercalcemia and hyperphosphatemia are at risk of precipitation of calcium-phosphate salts in soft tissues such as the kidney, cardiac conduction system, cornea, and basal ganglia. This most commonly occurs when the calcium-phosphate product is above 55.

  • Parathyroid hormone (PTH): Although ectopic hyperparathyroidism is very rare, coexisting primary hyperparathyroidism and cancer is fairly common. PTH may be mildly elevated in FHH as well; a 24 hour urinary calcium is useful for further evaluation in this situation.

  • Parathyroid hormone-related protein (PTHrP): PTHrP is elevated in HHM and undetectable in other causes of hypercalcemia. It may be helpful to measure PTHrP if the diagnosis of HHM cannot be made on clinical grounds or if the cause of hypercalcemia is unknown.

  • Vitamin D metabolites:1,25(OH) 2vitamin D should be measured when 1,25(OH) 2 vitamin D-secreting tumors or granulomatous disorders are considered in the differential diagnosis. 25 OH vitamin D should be measured if overdose of nutritional or over-the-counter vitamin D is suspected.

  • Basic metabolic profile: Creatinine, blood urea nitrogen, bicarbonate and chloride can be checked to evaluate renal function and hydration status.

Table I. Expected laboratory findings in tumor-induced hypercalcemia

Table I.

Expected laboratory findings in tumor-induced hypercalcemia
adjusted total or ionized calcium serum phosphorus (assuming normal renal function) PTH PTHrP 1,25(OH)2 vitamin D
elevated reduced reduced elevated reduced
elevated normal to elevated reduced reduced reduced
elevated normal to elevated reduced reduced elevated
elevated reduced elevated reduced variable

Other Tests That May Prove Helpful Diagnostically

  • Bone imaging studies such as a skeletal survey or a bone scan may be useful when assessing skeletal tumor burden in patients with known cancer and hypercalcemia.

  • Thyroid stimulating hormone (TSH) and free T4 may be checked to exclude hyperthyroidism as a cause of hypercalcemia.

  • Serum and urine protein electrophoresis (SPEP and UPEP) may be checked if multiple myeloma is suspected.

  • Vitamin A levels can be checked if toxicity is suspected.

  • 24 hour urinary calcium can help to differentiate causes of elevated PTH. It will be low in FHH but normal or elevated in primary or tertiary hyperparathyroidism and PTH-secreting tumors.

Management and Treatment of the Disease

Target the underlying cause

Management of hypercalcemia should be directed toward the underlying cause or combination of causes. For patients with cancer, the most effective long-term therapy is eradication of the tumor. Of course, sometimes treatment of hypercalcemia must begin before a diagnosis is made or before antineoplastic treatment has its effect.

Many patients with malignancy-associated hypercalcemia have dehydration and reduced renal function due to nephrogenic diabetes insipidus and decreased oral hydration from anorexia, nausea, and vomiting. The dehydration leads to a decrease in glomerular filtration rate, which further impairs renal calcium clearance. Renal calcium clearance may be increased by increasing the glomerular filtration rate (GFR) using aggressive hydration with saline, taking into account the level of dehydration as well as renal function, cardiovascular status, and severity of hypercalcemia.

The patient should be watched carefully for signs of fluid overload. Thiazide diuretics should be discontinued because they stimulate renal calcium reabsorption. Once the patient is adequately volume resuscitated and GFR is normal, a loop diuretic such as furosemide may be added to block renal calcium absorption and permit increased administration of saline.

In patients with HHM, local osteolysis, and PTH-secreting tumors hypercalcemia is primarily due to accelerated bone resorption. Treatment in these patients should include agents that block bone resorption, such as the intravenous bisphosphonates, zoledronate or pamidronate. If hypercalcemia is mild, it may be reasonable to wait to see the magnitude of calcium decrease with hydration first, though antiresorptive therapy with a bisphosphonate should be administered soon after discovery of hypercalcemia in patients with serum calcium above 12.0 mg/dl. Limiting oral calcium intake is not important in HHM and LOH, since intestinal calcium absorption is already low as a result of the low 1,25(OH) 2vitamin D concentrations and because cachexia is common in these patients.

Patients with 1,25(OH) 2 vitamin D-secreting tumors have hypercalcemia primarily due to increased GI absorption of calcium. In these patients, reducing or eliminating oral calcium and vitamin D intake and sunlight can be useful. Corticosteroid treatment to decrease calcitriol production and intestinal calcium absorption may be effective in these patients. Enhanced osteoclastic bone resorption is also a feature of 1,25(OH) 2vitamin D-secreting lymphomas, and IV bisphosphonates are helpful.

Factors which could worsen hypercalcemia should be avoided. These include dehydration, medications such as thiazide diuretics, prolonged inactivity, and excessive calcium intake of greater than 1000mg per day.

Saline rehydration

Saline rehydration is the initial treatment for all patients with malignancy-associated hypercalcemia. In general, isotonic saline should be administered at an initial rate of 200–300 ml/hr and adjusted to achieve urine output of 200 mL/ hour. Saline administration can lead to volume overload in patients who are unable to excrete the excess salt, particularly those with underlying cardiac or renal disease, so patients should be carefully monitored. Saline infusion should be stopped or slowed in patients who develop signs of fluid overload, and a loop diuretic may be used as necessary. Saline therapy may be sufficient to normalize the serum calcium concentration in mild hypercalcemia, but additional therapy is generally required for patients with MAHC.

Loop diuretics, such as furosemide 20-40 mg IV, should be added once the glomerular filtration rate is in the normal range to increase the renal excretion of calcium and avoid fluid overload.

Medications for treatment of hypercalcemia

Bisphosphonates

These anti-resorptive agents are the first-line medications for tumor-induced hypercalcemia. Absorption of oral bisphosphonates is poor, so only intravenously administered bisphosphonates are used for this indication. They have their peak effects in two to four days, so they should be administered in conjunction with treatments that result in more rapid reduction of hypercalcemia such as saline, furosemide, and possibly calcitonin. Bisphosphonates should be used with caution in patients with renal impairment. Repetitive use of intravenous bisphosphonates in patients with bone malignancies has been associated with increased risk of osteonecrosis of the jaw. More common adverse effects include flu-like symptoms (fevers, arthralgias, myalgia, and fatigue), impaired renal function, hypophosphatemia and hypocalcemia.

Potential secondary therapies

  • Gallium nitrateinhibits osteoclastic bone resorption and inhibits PTH secretion. It appears to be effective in PTHrP mediated and non-PTHrP mediated hypercalcemia, and it may be somewhat more effective than bisphosphonates alone. However, it must be administered via continuous infusion for five days (200 mg/m2/day), is not widely available, and has potential for nephrotoxicity.

  • Plicamycin, 25 mcg/kg administered over 4-6 hours for 3-8 doses, is also effective for treatment of tumor-induced hypercalcemia, but its use is limited by adverse effects including marrow suppression, hepatitis, and renal failure.

  • Cinacalcet is a calcimimetic agent which reduces the serum calcium concentration in patients with severe hypercalcemia due to parathyroid carcinoma. It is also indicated for use in primary hyperparathyroidism, though it is not part of standard therapy. It has not been studied in ectopic hyperparathyroidism.

  • In patients with 1,25 (OH) 2 vitamin D-mediated hypercalcemia, glucocorticoids, which decrease calcitriol production, are the first line of therapy after fluids and a low calcium diet. Glucocorticoid treatment (for example Prednisone 20-60 mg/day) generally reduces calcium concentrations within four to ten days

  • Calcitonin: While awaiting a bisphosphonate response in patients with severe hypercalcemia, calcitonin may be effective by decreasing bone resorption and increasing renal calcium excretion. The initial dose of salmon calcitonin is 4 international units/kg administered intramuscularly or subcutaneously every 12 hours. Doses may be increased to up to 8 IU/kg every 6 hours. Calcitonin has a rapid onset of action and lowers serum calcium by approximately 1.0 mg/dl [0.25 mmol/L] within 4-6 hours. It is generally well- tolerated except for mild nausea, flushing and rare hypersensitivity. However, tachyphylaxis develops rapidly with calcitonin such that it is of limited use after the first 48 hours.

Co-existing conditions which may affect treatment

  • Primary hyperparathyroidism and hypercalcemia of malignancy may coexist.

  • Patients receiving parenteral feeding who have tumor-induced hypercalcemia should use low calcium enteral feeding solutions. Oral calcium supplements should be discontinued.

  • Immobility can worsen hypercalcemia in high bone turnover states such as osteolysis. Weight-bearing mobility should be encouraged if possible.

  • A number of medications, including thiazide diuretics, lithium, calcium and vitamin D supplements, and calcitriol (for a more complete list, see "Other causes of hypercalcemia"), can precipitate or worsen hypercalcemia. These should be discontinued if possible.

  • Patients with altered mental status and hypercalcemia may benefit from decreasing or discontinuing use of sedating medications.

  • Hypophosphatemia often occurs in patients with hypercalcemia due to the phosphaturic effect of PTH and PTHrP, decreased nutritional intake, administration of large volumes of saline, loop diuretics, and anti-resorptive treatment. Hypophosphatemia may make it more difficult to treat the hypercalcemia. Phosphorus should be replaced enterally as neutral phosphate to a level of 2.5 – 3.0 mg/dL [0.98 – 1.0 mmol/L]. Calcium-phosphorus product should be maintained below 40 and renal function should be monitored during phosphate replacement. Due to risk of severe hypocalcemia and renal failure, intravenous phosphorus replacement should be avoided except when enteral administration is impossible and hypophosphatemia is very severe.

When to change therapy

Patients with tumor-related hypercalcemia are likely to have progression of hypercalcemia as the malignancy progresses. Patients with metastatic bone disease will receive regular IV bisphosphonates every 3-4 weeks to prevent skeletal complications, which will also help their hypercalcemia.

Hemodialysis against a low-calcium dialysate is effective in lowering serum calcium levels in patients with severe hypercalcemia whose renal failure limits aggressive saline administration and medications for treatment of hypercalcemia. Hemodialysis is not a definitive treatment, so it should be used in patients whose malignancies are likely to respond to anti-tumor therapy.

Treatment of hypercalcemia in patients with hypercalcemia associated with malignancy may not improve survival. If all available treatments for cancer have failed, withholding anti-hypercalcemic treatments, which will eventually result in coma and death, may be reasonable.

What’s the Evidence?/References

Are you sure the patient has tumor-induced hypercalcemia?

Shane, E, Irani, D, Favus, M. "Hypercalcemia: Pathogenesis, Clinical Manifestations, Differential Diagnosis, and Management". Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. American Society for Bone and Mineral Resesarch. 2006. pp. 176-80.

(Brief review of hypercalcemia including clinical manifestations.)

Bushinsky, DA, Monk, RD. "Electrolyte quintet: Calcium". The Lancet. vol. 352. 1998. pp. 306-11.

(Succinct review including sections about calcium homeostasis and symptoms of hypercalcemia.)

What else could the patient have?

Horwitz, MJ, Hodak, SP, Stewart, AF, Rosen, CJ. "Non-Parathyroid Hypercalcemia". Primer on the metabolic bone diseases and disorders of mineral metabolism. American Society for Bone and Mineral Research. 2008. pp. 307-12.

(Includes more detail about the differential diagnosis of hypercalcemia as well as more detail about the pathological processes in tumor-induced hypercalcemia.)

Harari, A, Waring, A, Fernandez-Ranvier, G, Hwang, J, Suh, I. "Parathyroid carcinoma: A 43-year outcome and survival analysis". J Clin Endocrinol Metab. vol. 96. 2011. pp. 3679-86.

(Good review about parathyroid carcinoma including outcomes.)

Clines, GA, Guise, TA. "Hypercalcemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone". Endocrine-Related Cancer. vol. 12. 2005. pp. 549-83.

(Detailed review of the bone physiology and pathophysiology of tumor-induced hypercalcemia.)

Mundy, GR. "Metastasis to bone: Causes, consequences and therapeutic opportunities". Nature Rev Cancer. vol. 2. 2002. pp. 584-92.

(Review of pathophysiology of bone metastases.)

Seymour, JF, Gagel, RF. "Calcitriol: The major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphoma". Blood. vol. 82. 1993. pp. 1383-94.

(Classic description of 1,25(OH)2vitamin D-secreting lymphomas.)

Key Laboratory and Imaging tests

Carroll, MF, Schade, DS. "A practical approach to hypercalcemia". Am Fam Physician. vol. 67. 2003. pp. 1959-66.

(A good review of the fundamentals of establishing a cause of hypercalcemia.)

Management and treatment of the disease

Stewart, AF. "Hypercalcemia associated with cancer". N Engl J Med. vol. 352. 2005. pp. 373-9.

(Review article focusing on management strategies.)

Santarpia, L, Koch, CA, Sarlis, NJ. "Hypercalcemia in cancer patients: Pathobiology and management". Horm Metab Res. vol. 42. 2010. pp. 153-64.

(Includes a useful table for adult and pediatric dosing, interactions and precautions of anti-hypercalcemic medications.)

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