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 (by measuring ionized calcium or calculating the ) 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 “homeostasis.” for details on calcium physiology and
Hypercalcemia is a total serum calcium concentration of > 10.5 mg/dL (> 2.62 mmol/L) or ionized (free) calcium concentration of > 5.25 mg/dL (> 1.31 mmol/L). 
- True hypercalcemia: ↑ ionized calcium or ↑ corrected calcium (regardless of total calcium level); can be symptomatic.
- Factitious hypercalcemia: ↑ total calcium with normal ionized (non-protein bound, physiologically active) calcium or normal corrected calcium level; asymptomatic.
|Causes of hypercalcemia |
|Types of hypercalcemia||Etiology||Pathophysiology|
|PTH-mediated hypercalcemia||Primary hyperparathyroidism|
|Familial hypocalciuric hypercalcemia|| |
|Non-PTH-mediated hypercalcemia||Hypercalcemia of malignancy|| |
|Granulomatous disorders (e.g., sarcoidosis)|
|Long periods of immobilization|
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
Immobilization, inherited (FHH)
Milk-alkali synd., meds (thiazides, lithium)
Neoplasm (multiple myeloma, breast, lung)
Excessive vitamin D
Excessive vitamin A
Sarcoidosis & granulomatous diseases
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.”
- Nephrolithiasis, nephrocalcinosis (calcium oxalate > calcium phosphate stones)
- Bone pain, arthralgias, myalgias, fractures
- Abdominal pain
- Nausea and vomiting
- Peptic ulcer disease 
- Neuropsychiatric symptoms such as anxiety, depression, fatigue, and cognitive dysfunction
- Diminished muscle excitability
- Polyuria and dehydration
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!
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.
- Mild hypercalcemia
- Moderate hypercalcemia
- Severe hypercalcemia, also known as hypercalcemic crisis
Subtypes and variants
Familial hypocalciuric hypercalcemia (FHH) 
- Etiology: : autosomal dominant inactivating mutation in the CaSR gene → decreased sensitivity of G-coupled calcium-sensing receptors in parathyroid glands and kidneys →; higher levels of Ca2+ required to suppress PTH and higher reabsorption of Ca2+ in the kidney → hypocalciuria with mild hypercalcemia and normal or increased PTH levels
- Clinical features
- Confirm true hypercalcemia: measure ionized calcium OR calculate using total calcium and serum albumin.
- Risk assessment and global evaluation
- Initial investigations of underlying etiology
- Intermediate investigations of underlying etiology: Consider these based on the results of initial investigations.
Advanced investigations of underlying etiology: Consider these based on combined results of the initial and intermediate investigations (see “Other investigations to consider” for details).
- ↑ PTHrP or ↑ 1,25-dihydroxyvitamin D: investigations for tumors, lymphoma, or granulomatous diseases
- Normal or ↓ PTHrP, and normal or ↓ vitamin D levels: investigations for multiple myeloma, thyrotoxicosis, Paget disease, vitamin A toxicity, or adrenal insufficiency
- ↓ Urine calcium excretion: investigations for FHH (e.g., genetic testing, see FHH)
- Adjunctive studies: consider on an individual basis (e.g., bone densitometry or detailed )
Severe or symptomatic hypercalcemia is a medical emergency. Treatment should be initiated immediately, in parallel with diagnostic workup.
Routine investigations 
- Serum calcium
- Other laboratory studies
- ECG findings may include:
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.
Investigations to determine underlying etiology
- Serum intact PTH
- Vitamin D levels
Assessment of urinary calcium excretion 
- Interpretation 
Measurement of serum intact PTH level is the key initial study for confirmed hypercalcemia with no immediately evident etiology.
Other investigations to consider 
- Laboratory studies
- All patients
Severe hypercalcemia and symptomatic moderate hypercalcemia: Admit to hospital and treat as a medical emergency.
- Rapidly lower calcium levels.
- Consider targeted therapy based on suspected etiology: e.g., surgery, calcimimetics, corticosteroids.
- Treat any complications: e.g., arrhythmias, nephrolithiasis.
- Consider hemodialysis for refractory life-threatening hypercalcemia or if other therapies are contraindicated (e.g., bisphosphonates in severe renal failure).
Mild hypercalcemia or asymptomatic moderate hypercalcemia: Consider inpatient vs. outpatient therapy on an individual basis.
- Acute treatment other than supportive care and treatment of the underlying cause is usually not necessary.
- Follow calcium levels and monitor for the development of symptoms. 
- Ensure adequate hydration.
- Reduce dietary intake of calcium.
- Avoid; potentially aggravating medications (e.g., thiazides; , lithium, vitamin D, calcidiol, calcitriol).
- Encourage mobility and avoid prolonged bed rest/inactivity. 
Fluid therapy and volume status management
- IV fluid repletion with 0.9% NaCl : typically 4–6 L in 24 hours
- Obtain serial calcium checks and monitor urine output and .
- Consider IV loop diuretic (e.g. IV furosemide ) ONLY if there are signs of volume overload (e.g., pulmonary congestion, significant peripheral edema). 
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 48 hours of use after
- Bisphosphonates for slow-onset, long-term control of hypercalcemia
- Hypercalcemia due to primary or tertiary hyperparathyroidism 
- Hypercalcemia due to lymphoma, granulomatous diseases, or vitamin D intoxication: systemic glucocorticoids (e.g., prednisone ) 
Alternative therapeutic options
- Hemodialysis may additionally be considered in the following circumstances:
Acute management checklist
- Confirm hypercalcemia (i.e., check ionized calcium and/or correct serum calcium for albumin).
- Initial diagnostic work-up: serum PTH, CBC, BMP, phosphate, alkaline phosphatase, and VBG
- Initiate immediate treatment in parallel with the diagnostic workup for severe or symptomatic hypercalcemia.
- Obtain IV access.
- Provide aggressive IV fluid repletion with isotonic saline.
- Give IV bisphosphonate.
- Consider SQ or IM calcitonin.
- Consider an IV loop diuretic (e.g. furosemide) ONLY if there are signs of fluid overload.
- Consider dialysis in severe, life-threatening hypercalcemia or if IV fluid repletion is contraindicated due to severe heart failure or oliguric AKI.
- Give glucocorticoids for hypercalcemia due to lymphoma, granulomatous diseases, or vitamin D intoxication.
- Consider surgical consult for hypercalcemia due to primary or tertiary hyperparathyroidism
- Monitor serum calcium levels, hydration status, and urine output.
- Discontinue potentially aggravating medications (e.g., thiazides, lithium, vitamin D, calcium supplements).
- Reduce dietary intake of calcium.
- Encourage mobility.
- Identify and treat other underlying causes of hypercalcemia (see “ ”).
- Consider consulting endocrinology, nephrology, and/or oncology as needed.