Hypercalcaemia of malignancy

Overview

•PTHrP-mediated (humoral) - 80% of cases: tumour cells secrete PTHrP, which binds PTH/PTHrP receptor → increased osteoclast activity + renal calcium reabsorption; elevated calcium suppresses endogenous PTH → PTHrP elevated, PTH suppressed, phosphate low

•Cancers: squamous cell lung cancer, renal cell carcinoma, breast cancer, endometrial cancer

•Osteolytic bone metastases: direct tumour invasion stimulates local osteoclast activity via cytokines (RANKL); PTH suppressed; breast cancer and multiple myeloma

•Autonomous vitamin D production: lymphoma macrophages convert 25-OH vitamin D → 1,25-dihydroxyvitamin D (calcitriol) via 1-alpha-hydroxylase → excess intestinal calcium absorption; same mechanism as sarcoidosis

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Key discriminator: in PTHrP-mediated hypercalcaemia PTH is suppressed and PTHrP is elevated. In primary hyperparathyroidism PTH is elevated - biochemistry is how you tell them apart.

Presentation

•Stones - renal colic, nephrolithiasis

•Bones - bone pain, arthralgia, myalgia, pathological fractures

•Abdominal groans - nausea, vomiting, constipation, pancreatitis

•Thrones - polyuria and polydipsia (high calcium impairs ADH action → nephrogenic DI → dehydration → reduced GFR → worsening hypercalcaemia)

•Psychic overtones - confusion, lethargy, depression

•ECG: shortened QT interval; can progress to life-threatening arrhythmias at very high levels

Investigations

•Adjusted serum calcium - corrected Ca = total Ca + 0.02 × (40 - albumin g/L); hypoalbuminaemia in cancer can mask true hypercalcaemia

•PTH - suppressed in PTHrP-mediated hypercalcaemia

•PTHrP - elevated; confirms humoral mechanism

•Serum phosphate - low (PTHrP reduces renal tubular phosphate reabsorption)

•Renal function - assess for AKI; required before bisphosphonates

•ECG - shortened QT interval

•1,25-dihydroxyvitamin D - elevated in lymphoma or granulomatous disease (e.g. sarcoidosis)

Differential diagnosis

Key differentials for hypercalcaemia
FeatureMalignancy (PTHrP)Primary hyperparathyroidismSarcoidosis
PTHSuppressedElevatedSuppressed
PTHrPElevatedNormalNormal
PhosphateLowLowNormal/low
1,25-OH vitamin DNormal/lowNormalElevated
OnsetRapid, severeChronic, slowVariable

Feature	Malignancy (PTHrP)	Primary hyperparathyroidism	Sarcoidosis
PTH	Suppressed	Elevated	Suppressed
PTHrP	Elevated	Normal	Normal
Phosphate	Low	Low	Normal/low
1,25-OH vitamin D	Normal/low	Normal	Elevated
Onset	Rapid, severe	Chronic, slow	Variable

Management

•Severe hypercalcaemia (>3.5 mmol/L) or severe symptoms - emergency hospital admission

🥇 First-line

•IV 0.9% normal saline rehydration - restores GFR and increases renal calcium excretion

•Bisphosphonates (e.g. zoledronic acid) - inhibit osteoclast activity; administer after adequate rehydration; check renal function first

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Discharge advice: increase fluid intake to 3-4 L/day (where no contraindication e.g. heart failure, severe renal impairment). A low calcium diet is NOT recommended - intestinal calcium absorption is already reduced in malignancy. Encourage mobilisation and advise to report recurrence of symptoms.

•Avoid drugs that exacerbate hypercalcaemia: thiazide diuretics, calcium supplements, high-dose vitamin D

•Calcium-lowering treatment is temporising - hypercalcaemia typically recurs within 1-4 weeks if underlying cancer is not treated