Hypercalcemia of malignancy

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Last reviewed: 4 Apr 2025

Last updated: 18 Jul 2023

Hypercalcemia of malignancy can result from: humoral hypercalcemia of malignancy (characterized by tumor secretion of parathyroid hormone-related peptide [PTHrP]); local osteolytic hypercalcemia (characterized by local release of factors, including PTHrP, by bony metastases that promote osteoclast differentiation and function); calcitriol (1,25-dihydroxyvitamin D)-mediated hypercalcemia (characterized by autonomous production of calcitriol [(1,25-dihydroxyvitamin D)] by lymphoma cells); and ectopic hyperparathyroidism (characterized by tumor production of parathyroid hormone [PTH]), which is very rare.

Pharmacologic therapy can transiently improve hypercalcemia. However, sustained maintenance of normocalcemia requires eradication of underlying malignancy.

Treatment options include intravenous bisphosphonates, denosumab, calcitonin, glucocorticoids (for calcitriol [1,25-dihydroxyvitamin D]-mediated hypercalcemia), and calcimimetics (for ectopic PTH production).

Definition

Hypercalcemia occurs in 20% to 30% of patients with cancer.[1][2] Cancer represents the most common etiology of hypercalcemia in the inpatient setting.[3] It can result from: humoral hypercalcemia of malignancy (characterized by tumor secretion of parathyroid hormone-related peptide [PTHrP]); local osteolytic hypercalcemia (characterized by local release of factors, including PTHrP, by bony metastases that promote osteoclast differentiation and function); calcitriol (1,25-dihydroxyvitamin D)-mediated hypercalcemia (characterized by autonomous production of calcitriol [(1,25-dihydroxyvitamin D)] by lymphoma cells); and ectopic hyperparathyroidism (characterized by tumor production of parathyroid hormone), which is very rare.[4][5]

History and exam

Key diagnostic factors

history of malignancy

Full details

Other diagnostic factors

normal physical exam
poor skin turgor and/or dry mucous membranes
confusion
fatigue
constipation
loss of appetite
nausea
polyuria
polydipsia
bone pain
use of hypercalcemia-inducing medication
stupor
coma

Full details

Risk factors

nonmetastatic malignancy
metastatic skeletal involvement
lymphoma

Full details

Diagnostic tests

1st tests to order

total serum calcium
serum ionized calcium
serum albumin
comprehensive metabolic panel
resting ECG
serum intact parathyroid hormone
serum parathyroid hormone-related peptide
serum phosphorus
serum calcitriol (1,25-dihydroxyvitamin D)
serum 25-hydroxyvitamin D

Full details

Tests to consider

skeletal survey
chest x-ray

Full details

Treatment algorithm

ACUTE

mild hypercalcemia or asymptomatic moderate hypercalcemia

symptomatic moderate or severe hypercalcemia: without advanced kidney disease

symptomatic moderate or severe hypercalcemia: with advanced kidney disease

Contributors

Authors

Albert Shieh, MD

Assistant Professor of Medicine

Division of Geriatric Medicine

Department of Medicine

University of California, Los Angeles

Los Angeles

Disclosures

AS declares that he has no competing interests.

Dorothy Martinez, MD

Clinical Professor of Medicine

Division of Endocrinology

Department of Medicine

University of California, Los Angeles

Los Angeles

Disclosures

DM declares that she has no competing interests.

Peer reviewers

Ken C. Chiu, MD, FACE

Professor

Endocrinology Fellowship Training Program

Department of Clinical Diabetes, Endocrinology, and Metabolism

City of Hope National Medical Center

Duarte

Disclosures

KCC declares that he has no competing interests.

Richard Quinton, MD

Consultant and Senior Lecturer

Endocrine Unit

Newcastle University and Royal Victoria Infirmary

Newcastle-upon-Tyne

Disclosures

RQ has been reimbursed by Amgen, the manufacturer of Cinacalcet, for attending a conference and for giving an educational seminar (total under £1,200 over past 3 years).

References

Our in-house evidence and editorial teams collaborate with international expert contributors and peer reviewers to ensure that we provide access to the most clinically relevant information possible.

Key articles

Cancer Institute NSW. Hypercalcaemia of malignancy (HCM). Jul 2019 [internet publication].Full text

Guise TA, Wysolmerski JJ. Cancer-associated hypercalcemia. N Engl J Med. 2022 Apr 14;386(15):1443-51. Abstract

Horwitz MJ. Chapter 84: Non-parathyroid hypercalcemia. In: Bilezikian JP, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 9th ed. Washington, DC: American Society of Bone and Mineral Research; 2018:639-45.

El-Hajj Fuleihan G, Clines GA, Hu MI, et al. Treatment of hypercalcemia of malignancy in adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2023 Feb 15;108(3):507-28.Full text Abstract

Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005 Jan 27;352(4):373-9. Abstract

Alberta Provincial Tumour Council. Oncologic emergencies: a guide for family physicians. Sep 2014 [internet publication].Full text

Society for Endocrinology. Emergency management of acute hypocalcaemia in adult patients. Sep 2016 [internet publication].Full text

Horwitz MJ, Hodak SP, Steward AF. Non-parathyroid hypercalcemia. In: Rosen CJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 8th ed. Washington, DC: American Society of Bone and Mineral Research; 2013:562-71.

Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001 Jan 15;19(2):558-67. Abstract

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

Differentials
- Primary hyperparathyroidism
- Hyperthyroidism
- Adrenal insufficiency
More Differentials
Guidelines
- Cancer guidelines: symptom management. Oncologic emergencies
- Treatment of hypercalcemia of malignancy in adults: an Endocrine Society clinical practice guideline
More Guidelines
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Hypercalcemia of malignancy

Summary

Definition

History and exam

Key diagnostic factors

Other diagnostic factors

Risk factors

Diagnostic tests

1st tests to order

Tests to consider

Treatment algorithm

mild hypercalcemia or asymptomatic moderate hypercalcemia

symptomatic moderate or severe hypercalcemia: without advanced kidney disease

symptomatic moderate or severe hypercalcemia: with advanced kidney disease

Contributors

Authors

Albert Shieh, MD

Disclosures

Dorothy Martinez, MD

Disclosures

Peer reviewers

Ken C. Chiu, MD, FACE

Disclosures

Richard Quinton, MD

Disclosures

References

Key articles

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

Differentials

Guidelines

Log in or subscribe to access all of BMJ Best Practice

Log in or subscribe to access all of BMJ Best Practice

Log in to access all of BMJ Best Practice