What causes hypercalcemia (elevated calcium levels)?

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From the Guidelines

High calcium levels in the blood, known as hypercalcemia, are most commonly caused by hyperparathyroidism, where overactive parathyroid glands produce too much parathyroid hormone, as well as by cancer, particularly bone metastases, lung cancer, and multiple myeloma, which can release calcium from affected bones 1.

Causes of Hypercalcemia

The causes of hypercalcemia can be multifactorial and include:

  • Hyperparathyroidism, which is characterized by the overproduction of parathyroid hormone, leading to an increase in calcium levels in the blood 1
  • Cancer, including bone metastases, lung cancer, and multiple myeloma, which can release calcium from affected bones into the bloodstream 1
  • Certain medications, such as thiazide diuretics, lithium, and excessive vitamin D supplements, which can contribute to elevated calcium levels 1
  • Endocrine disorders, such as hyperthyroidism, which can also lead to hypercalcemia 1
  • Granulomatous diseases, like sarcoidosis and tuberculosis, which can cause an increase in calcium levels 1
  • Prolonged immobilization, which can lead to an increase in calcium release from bones into the bloodstream 1
  • Kidney failure, which can reduce calcium excretion and contribute to hypercalcemia 1

Symptoms and Treatment

Symptoms of hypercalcemia include fatigue, weakness, increased thirst and urination, digestive issues, bone pain, and cognitive changes. Treatment depends on the underlying cause and may include addressing the primary condition, increasing fluid intake, medications like bisphosphonates or calcitonin to lower calcium levels, and in severe cases, hospitalization for intravenous fluids and medications 1.

Prevention and Management

Prevention and management of hypercalcemia involve avoiding hypercalcemia, particularly in patients with chronic kidney disease (CKD) stages G3a to G5D, and using a dialysate calcium concentration between 1.25 and 1.50 mmol/L (2.5 and 3.0 mEq/L) in patients with CKD stage G5D 1.

From the FDA Drug Label

Hypercalcemia associated with cancer The FDA drug label mentions hypercalcemia as a condition associated with cancer.

  • The cause of high calcium mentioned is:
    • Cancer 2

From the Research

Causes of High Calcium

  • Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia, accounting for approximately 90% of cases 3, 4
  • Malignancy is another major cause of hypercalcemia, with various mechanisms involved, such as production of parathyroid hormone-related protein (PTHrP) or activation of osteoclast degradation of bone 5, 6, 7
  • Other causes of hypercalcemia include:
    • Granulomatous disease, such as sarcoidosis 3, 4
    • Endocrinopathies, such as thyroid disease 3
    • Immobilization 3
    • Genetic disorders 3
    • Medications, such as thiazide diuretics and supplements, including calcium, vitamin D, or vitamin A 3
    • Vitamin D toxicity 4
    • Milk alkali syndrome 4
    • Multiple myeloma 4
    • Tuberculosis 4
    • Chronic kidney disease 4
    • Lymphoma 4, 7
    • Sodium-glucose cotransporter 2 protein inhibitors 3
    • Immune checkpoint inhibitors 3
    • Denosumab discontinuation 3
    • SARS-CoV-2 3
    • Ketogenic diets 3
    • Extreme exercise 3

Mechanisms of Hypercalcemia

  • Excessive production of parathyroid hormone (PTH) or PTHrP 3, 5, 7
  • Activation of osteoclast degradation of bone 5, 6
  • Extrarenal activation of vitamin D 5
  • Ectopic PTH secretion 5, 7
  • Cosecretion of PTHrP and 1,25-dihydroxyvitamin D (1,25(OH)2D) 7

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Hypercalcemia: A Review.

JAMA, 2022

Research

A Review of Current Clinical Concepts in the Pathophysiology, Etiology, Diagnosis, and Management of Hypercalcemia.

Medical science monitor : international medical journal of experimental and clinical research, 2022

Research

Hypercalcemia and cancer: Differential diagnosis and treatment.

CA: a cancer journal for clinicians, 2018

Research

Hypercalcemia in non-Hodgkin's lymphoma due to cosecretion of PTHrP and 1,25-dihydroxyvitamin D.

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 2021

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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