Hypercalcaemia of Malignancy | Management

Introduction
Hypercalcaemia is defined as an adjusted serum calcium of >2.6 mmol/L.1 While there are various causes of hypercalcaemia, this will focus on hypercalcaemia associated with malignancy.
Hypercalcaemia of malignancy is the most common life-threatening metabolic disorder in cancer patients and occurs in 10-20% of patients with advanced cancers.2

Aetiology
Three main mechanisms result in hypercalcaemia of malignancy:

Secretion of parathyroid hormone-related protein (PTHrP)
Osteolytic metastases
Secretion of 1,25-dihydroxyvitamin D (calcitriol)

Depending on the cancer, hypercalcaemia may occur via one or a combination of these mechanisms.1
PTHrP secretion is the most common cause of hypercalcaemia in malignancy. It is generally associated with renal cancer, ovarian cancer, endometrial cancer and squamous cell carcinoma. PTHrP stimulates osteoclastic resorption and inhibits osteoblast formation of bone, resulting in excessive calcium release from the skeleton. It also acts in the kidney to reduce calcium clearance, further increasing calcium levels in the blood.
Breast cancer and multiple myeloma are associated with osteolytic metastases. Local release of cytokines and chemokines results in increased osteoclast activity. This excessive calcium release overwhelms the kidney’s ability to clear it from the body.
Calcitriol-mediated hypercalcaemia can occur in most lymphomas. There is overexpression of 1-alpha hydroxylase, the enzyme responsible for converting 25-hydroxyvitamin D to calcitriol. This leads to excessive production of calcitriol (the active form of vitamin D), resulting in increased intestinal absorption of calcium and increased osteoclast activity.

Risk factors
The main risk factor for hypercalcaemia of malignancy is the type of cancer the patient has. While hypercalcaemia can occur in any cancer, there are some types that it is more associated with:1

Some medications can also worsen hypercalcaemia, including thiazide diuretics, lithium and over-the-counter supplements containing calcium or vitamin D.

Clinical features
History
Hypercalcaemia often presents with vague symptoms:3

Confusion
Nausea and vomiting
Fatigue
Thirst: due to increased urine production causing dehydration
Polyuria: due to increased urine production via nephrogenic diabetes insipidus
Constipation
Anorexia
Bone pain: either due to the hypercalcaemia or due to bony metastases 
Abdominal pain
Renal colic

Stones, bones, groans and psychiatric moans
The common presenting features are often remembered as stones, bones, groans and psychiatric moans (renal calculi, bone pain, abdominal pain and psychiatric features).
However, patients can often present with minimal symptoms or may be asymptomatic if the hypercalcaemia is mild. 

Clinical examination
Few examination findings are specific to hypercalcaemia. There may be findings related to the underlying cancer (e.g. lymphadenopathy or hepatosplenomegaly). Typical examination findings may include:3

Signs of dehydration: dry mucous membranes, sunken eyes, reduced skin turgor
Hyporeflexia
Tongue fasciculations
Abdominal distension due to constipation
Bony tenderness

Investigations
The key investigation is the adjusted serum calcium level, with a result >2.6 mmol/L considered abnormal. Hypercalcaemia can then be further categorised according to severity:1

Mild: <3.0 mmol/L
Moderate: 3 – 3.5 mmol/L
Severe: >3.5 mmol/L

Other investigations are important to assess the cause and complications of hypercalcemia.
Bedside investigations
Relevant bedside investigations include:

ECG: hypercalcaemia can lead to abnormalities such as bradycardia, shortened QT interval and heart block

Laboratory investigations
Relevant laboratory investigations include:

Urea & electrolytes: renal function is necessary for planning treatment; AKI is a complication of hypercalcaemia
Parathyroid hormone (PTH): to help identify a cause of hypercalcaemia (PTH will often be suppressed in malignancies producing PTHrP)
Parathyroid hormone-related protein (PTHrP): to help identify a cause of hypercalcaemia (request if initial PTH level is low)
Phosphate (usually reported as part of a bone profile): hypercalcaemia can also be associated with hyperphosphatouria and hypophosphataemia due to the action of PTHrP
Calcitriol: to help identify a cause of hypercalcaemia (request if initial PTH is low in a patient with known lymphoma)
Vitamin D: deficiency may need to be corrected before administration of treatment
Immunoglobulins and electrophoresis: if underlying myeloma is suspected

Imaging investigations
Relevant imaging investigations include:

Chest X-ray: if underlying lung cancer is suspected
CT scan: to help stage any underlying cancer or assess for bony metastases

Management
Management of hypercalcaemia involves supportive measures to manage any associated symptoms/complications, stopping any medications that may be contributing and specific measures.
Medications for associated symptoms may include laxatives for constipation, anti-emetics for nausea and vomiting and analgesia for bone pain. 
Any medications contributing to hypercalcaemia should be stopped (thiazide diuretics, calcium supplements, vitamin D supplements and lithium). Medications that can worsen renal function (e.g. NSAIDs and ACE inhibitors) should also be reviewed and potentially withheld.
Specific measures to combat hypercalcaemia consist of rehydration and administration of bisphosphonates.
Rehydration
Asymptomatic patients with adjusted calcium <3 mmol/L can be considered for outpatient management, but most will require admission. Rehydration will often require IV fluids with a target of at least three litres in the first 24 hours (unless the patient has comorbidities that put them at risk of fluid overload).
Bisphosphonates
In hypercalcaemia generally, rehydration may be an adequate treatment for mild hypercalcaemia. However, hypercalcaemia of malignancy is much more likely to recur rapidly without bisphosphonates. 
IV zoledronic acid is generally the first-line bisphosphonate used, and pamidronate is the second-line, although this will vary between hospitals. The dose given may need to be adjusted based on the patient’s renal function.
Table 1. Bisphosphonates for hypercalcaemia of malignancy. 

Drug
Zoledronic acid
Disodium pamidronate

Dose (IV)
4mg
30mg to 90mg (depending on serum calcium)

Onset of effect
<4 days
<3 days

Maximum effect
4 to 7 days
5 to 7 days

Duration of effect
4 weeks
2-3 weeks

Note: bisphosphonates do not immediately reduce serum calcium levels, and the dose should not be repeated until at least day 5.
Serum calcium levels should be monitored, and if hypercalcaemia persists after 7 days, further bisphosphonate doses or denosumab (off-license) can be considered under specialist advice.

Complications
Complications of hypercalcaemia of malignancy include:

Hypercalcaemia is also a poor prognostic indicator for patients with cancer, with a mean survival of 2-3 months.4 This is not necessarily directly due to hypercalcaemia but because it tends to represent an advanced cancer stage.

Key points

Hypercalcaemia is a potentially life-threatening metabolic disorder occurring in 10-20% of patients with advanced cancers
Symptoms are often vague but commonly include nausea, constipation, abdominal pain and confusion
Diagnosis is based on adjusted serum calcium >2.6 mmol/L, and it can be classified as mild, moderate or severe depending on the exact level
Treatment consists of aggressive hydration with intravenous fluids and administration of bisphosphonates
Complications of hypercalcaemia include AKI, pancreatitis, arrhythmias and seizures
It is generally a poor prognostic indicator, with mean survival being around 2-3 months

Editor
Dr Chris Jefferies

References

BMJ Best Practice. Hypercalcaemia of malignancy. Published 2023. Available from: [LINK]
Scottish Palliative Care Guidelines. Hypercalcaemia. Published 2021. Available from: [LINK]
RCEM Learning. Hypercalcaemia in malignancy. Published 2021. Available from: [LINK]
NICE CKS. Hypercalcaemia: What is the prognosis? Published 2019. Available from: [LINK]

 

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