Last updated: September 11, 2023

Summarytoggle arrow icon

Hypercalcemia refers to high serum calcium levels (total Ca > 10.5 mg/dL or ionized Ca2+ > 5.25 mg/dL). The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy involving paraneoplastic production of parathyroid hormone-related protein (PTHrP). Manifestations of hypercalcemia include nephrolithiasis, bone pain, abdominal pain, polyuria, muscle weakness, and neuropsychiatric symptoms. The most important initial diagnostic steps are ruling out factitious hypercalcemia (by measuring ionized calcium or calculating the corrected calcium) and measuring intact PTH levels (to differentiate between PTH-mediated hypercalcemia and non-PTH-mediated hypercalcemia). Management depends on the severity of the calcium imbalance. Mild and asymptomatic moderate hypercalcemia is treated with oral rehydration and low calcium intake, while symptomatic or severe hypercalcemia is a potentially life-threatening medical emergency requiring hospitalization and immediate treatment with IV fluid repletion and medications that inhibit bone resorption (e.g., calcitonin, bisphosphonates). In addition, identification and treatment of the underlying cause of hypercalcemia are essential.

See “Hypocalcemia” for details on calcium physiology and homeostasis.

Definitiontoggle arrow icon

Etiologytoggle arrow icon

Hypercalcemia may be due to PTH-mediated or non-PTH-mediated causes. Primary hyperparathyroidism and malignancy are the most common causes, accounting for ∼ 90% of all cases. [2]

Causes of hypercalcemia [2][3]
Types of hypercalcemia Etiology Pathophysiology
PTH-mediated hypercalcemia Primary hyperparathyroidism
Tertiary hyperparathyroidism
Familial hypocalciuric hypercalcemia
  • See “Familial hypocalcuric hypercalcemia” in “Subtypes and variants.”
  • Lithium reduces renal calcium excretion and alters the PTH secretion set point [5][6]
Non-PTH-mediated hypercalcemia Hypercalcemia of malignancy
Granulomatous disorders (e.g., sarcoidosis)
Long periods of immobilization
Milk-alkali syndrome
Adrenal insufficiency
  • The exact pathophysiology is unknown; several mechanisms have been proposed. [10]

Severe/symptomatic hypercalcemia usually develops acutely and is typically caused by excessive osteoclast-mediated bone resorption, most commonly in association with malignancy.In primary hyperparathyroidism, serum calcium is typically lower and rises more slowly than in hypercalcemia of malignancy. Patients are, therefore, less symptomatic.

For causes of hypercalcemia, remember “Thinking Chimpanzees!”
Thinking: Thiazides, thyroid
Calcium supplementation
Immobilization, inherited (FHH)
Milk-alkali synd., meds (thiazides, lithium)
Paraneoplastic PTHrP
Adrenal insufficiency
Neoplasm (multiple myeloma, breast, lung)
Zollinger-Ellison syndrome
Excessive vitamin D
Excessive vitamin A
Sarcoidosis & granulomatous diseases

Clinical featurestoggle arrow icon

The clinical presentation is variable and ranges from asymptomatic presentation in mild hypercalcemia to life-threatening clinical features in severe hypercalcemia. See “Classification of hypercalcemia.” [6][11]

Hypercalcemia can cause pancreatitis. Hypocalcemia in patients with pancreatitis suggests pancreatic necrosis.

The presentation of hypercalcemia includes stones (nephrolithiasis), bones (bone pain, arthralgias), thrones (increased urinary frequency), groans (abdominal pain, nausea, vomiting), and psychiatric overtones (anxiety, depression, fatigue). Note that these are also the findings of vitamin D overdose!

Acute hypercalcemia is more likely to present with symptoms, whereas hypercalcemia that has progressed over time is more likely to be asymptomatic.

Classificationtoggle arrow icon

Laboratory values and the presence of symptoms should be used in conjunction to determine the need for treatment. Acutely symptomatic moderate hypercalcemia and severe hypercalcemia are medical emergencies and require hospital admission and immediate initiation of treatment.

Subtypes and variantstoggle arrow icon

Familial hypocalciuric hypercalcemia (FHH) [13]

Diagnosticstoggle arrow icon

Approach [1][2][3][5][6]

Severe or symptomatic hypercalcemia is a medical emergency. Treatment should be initiated immediately, in parallel with diagnostic workup.

Routine evaluation [2][5]

The corrected calcium concentration, calculated using serum albumin, may not be accurate in the setting of major acid-base imbalances. In patients with significant alkalemia or acidemia, it is recommended to measure ionized calcium directly.

Evaluation to determine underlying etiology

Measurement of serum intact PTH level is the key initial study for confirmed hypercalcemia with no immediately evident etiology.

Other evaluation to consider [1][5]

Treatmenttoggle arrow icon

Approach [2][5]

Supportive care

Fluid therapy and volume status management

Thiazide diuretics enhance Tubular calcium upTake: Discontinue them in hypercalcemia. Loop diuretics Lose calcium: They may be used to treat fluid overload in patients with hypercalcemia.

Standard pharmacotherapy

Pharmacotherapy is aimed at inhibiting bone resorption.

  • Consider calcitonin for rapid-onset, short-term control of hypercalcemia.
    • Reduces serum calcium within 2–6 hours, with maximal effect within 12–24 hours
    • Often limited by tachyphylaxis after 48 hours of use
  • Bisphosphonates for slow-onset, long-term control of hypercalcemia
    • Options
    • Typically lead to normalization of serum calcium within 2–4 days, with effect duration of days to weeks following a single dose
    • The dose may be repeated, if needed, after a minimum of 7 days.
    • Contraindicated in severe CKD (CrCl < 30 mL/min)

Alternative therapeutic options

These treatment options may be considered if hypercalcemia is resistant to other measures or the use of bisphosphonates is contraindicated due to severe renal failure.

  • Denosumab [2][5][23]
  • Hemodialysis may additionally be considered in the following circumstances:
    • Aggressive fluid repletion is contraindicated (e.g., patients with fluid overload due to severe heart failure or oliguric AKI).
    • Immediate reduction of calcium levels is necessary due to life-threatening symptomatic hypercalcemia. [24]

Targeted therapies

Acute management checklisttoggle arrow icon

Referencestoggle arrow icon

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  3. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical ; 2018
  4. Efremidou et al. Peptic Ulcer Perforation as the First Manifestation of Previously Unknown Primary Hyperparathyroidism. Case Reports in Gastroenterology. 2007; 1 (1): p.21-26.doi: 10.1159/000104224 . | Open in Read by QxMD
  5. Endotext [Internet]. Updated: October 29, 2019. Accessed: June 25, 2020.
  6. Renaghan AD, Rosner MH. Hypercalcemia: etiology and management. Nephrology Dialysis Transplantation. 2018; 33 (4): p.549-551.doi: 10.1093/ndt/gfy054 . | Open in Read by QxMD
  7. Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcaemia. BMJ. 2015; 350 (jun02 15): p.h2723-h2723.doi: 10.1136/bmj.h2723 . | Open in Read by QxMD
  8. Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surgery. 2016; 151 (10): p.959.doi: 10.1001/jamasurg.2016.2310 . | Open in Read by QxMD
  9. Christensen SE, Nissen PH, Vestergaard P, Heickendorff L, Brixen K, Mosekilde L. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf). 2008; 69 (5): p.713-720.doi: 10.1111/j.1365-2265.2008.03259.x . | Open in Read by QxMD
  10. Foley KF, Boccuzzi L. Urine Calcium: Laboratory Measurement and Clinical Utility. Lab Med. 2010; 41 (11): p.683-686.doi: 10.1309/lm9so94znbhedntm . | Open in Read by QxMD
  11. Arnold A, Agarwal SK, and Thakker RV.. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ninth Edition. John Wiley & Sons, Inc. All rights reserved ; 2018
  12. Khan AA, Hanley DA, Rizzoli R, et al. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporosis International. 2016; 28 (1): p.1-19.doi: 10.1007/s00198-016-3716-2 . | Open in Read by QxMD
  13. LeGrand SB, Leskuski D, Zama I. Narrative Review: Furosemide for Hypercalcemia: An Unproven yet Common Practice. Ann Intern Med. 2008; 149 (4): p.259.doi: 10.7326/0003-4819-149-4-200808190-00007 . | Open in Read by QxMD
  14. Walsh J, Gittoes N, Selby P, __. Society for Endocrinology Endocrine Emergency Guidance: Emergency management of acute hypercalcaemia in adult patients. Endocrine Connections. 2016; 5 (5): p.G9-G11.doi: 10.1530/ec-16-0055 . | Open in Read by QxMD
  15. Basok AB, Rogachev B, Haviv YS, Vorobiov M. Treatment of extreme hypercalcaemia: the role of haemodialysis. BMJ Case Reports. 2018: p.bcr-2017-223772.doi: 10.1136/bcr-2017-223772 . | Open in Read by QxMD
  16. Bilezikian JP, Khan AA, Silverberg SJ, et al. Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. J Bone Miner Res. 2022.doi: 10.1002/jbmr.4677 . | Open in Read by QxMD
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  22. Conaway HH, Henning P, Lerner UH. Vitamin A Metabolism, Action, and Role in Skeletal Homeostasis. Endocr Rev. 2013; 34 (6): p.766-797.doi: 10.1210/er.2012-1071 . | Open in Read by QxMD
  23. Yoon HE, Kim TY, Lee S, et al. Adrenal insufficiency presenting as hypercalcemia and acute kidney injury. International Medical Case Reports Journal. 2016; Volume 9: p.223-226.doi: 10.2147/imcrj.s109840 . | Open in Read by QxMD
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  26. ROBINSON PJ, CORRALL RJM. The importance of distinguishing familial hypocalciuric hypercalcaemia from asymptomatic primary hyperparathyroidism prior to neck exploration. Clin Otolaryngol Allied Sci. 1990; 15 (2): p.141-146.doi: 10.1111/j.1365-2273.1990.tb00447.x . | Open in Read by QxMD
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