Hypercalcaemia Pharmacotherapy

Hypercalcaemia pharmacotherapy lowers serum calcium by restoring fluid, blocking bone resorption and reducing intestinal absorption. Mild hypercalcaemia is corrected calcium 2.6 to 3.0 mmol/L, moderate 3.0 to 3.5 mmol/L and severe over 3.5 mmol/L. Commonest causes are primary hyperparathyroidism and cancer.

Classification. Fluids; bisphosphonates; denosumab; calcitonin; glucocorticoids; calcimimetics; dialysis.

Mechanism. Saline expands volume and promotes calcium excretion in the urine. Bisphosphonates and denosumab inhibit osteoclast activity and bone resorption. Calcitonin acts rapidly on osteoclasts and the kidney. Glucocorticoids reduce vitamin D activation by lymphoma cells and granulomas. Cinacalcet lowers parathyroid hormone release.

Loop diuretics. Use furosemide only after volume is restored and only if there is overload. It is no longer routine.

Stop contributors. Calcium and vitamin D supplements, thiazides, lithium, and excessive antacids.

Renal adjustment. Zoledronic acid doses fall in kidney impairment (creatinine clearance 30 to 60 mL/minute: reduced dose); avoid under 30 mL/minute. Use denosumab instead.

• First-line. Intravenous fluids, then a bisphosphonate for cancer-related hypercalcaemia; surgery for primary hyperparathyroidism.
• Alternative. Denosumab for bisphosphonate-refractory disease or kidney failure; cinacalcet when surgery is unsuitable.
• Specialist. Glucocorticoids for lymphoma, myeloma or granulomatous disease; dialysis; parathyroidectomy.
• Emergency. Severe hypercalcaemia with confusion, dehydration, arrhythmia or AKI.

Selection. Always restore volume first. Add a bisphosphonate within 24 hours for malignancy. Add calcitonin for rapid effect in severe cases.

Contraindications. Bisphosphonates: hypocalcaemia, severe kidney failure (zoledronic acid), pregnancy. Denosumab: hypocalcaemia. Calcitonin: hypersensitivity. Large saline volumes: heart failure.

Serious adverse effects.

• Hypocalcaemia, hypophosphataemia and hypomagnesaemia.
• Acute phase reaction (fever, bone pain) with bisphosphonates; kidney injury; osteonecrosis of the jaw with repeated doses; atypical femoral fractures with long courses.
• Severe hypocalcaemia with denosumab, especially in kidney failure.
• Nausea, flushing and tachyphylaxis with calcitonin.

Major interactions. Aminoglycosides and NSAIDs with bisphosphonates (kidney injury); loop diuretics and digoxin (electrolyte effects); thiazides and calcium supplements raise calcium; cinacalcet with CYP2D6 substrates.

Common prescribing errors.

• Giving bisphosphonates to a dehydrated patient.
• Using furosemide before volume repletion.
• Missing vitamin D and calcium deficiency after treatment.
• Dosing zoledronic acid without checking creatinine clearance.
• Failing to treat the underlying cause.

Special groups.

• Pregnancy: avoid bisphosphonates and denosumab; use fluids and specialist care.
• Breastfeeding: avoid.
• Children: specialist care only.
• Older adults: monitor volume and kidney function.
• Kidney: denosumab and dialysis preferred in severe impairment.
• Liver: no adjustment.
• East Africa: myeloma, advanced cancers and tuberculosis (granulomatous hypercalcaemia) are plausible causes; zoledronic acid and denosumab are costly and often limited to referral centres, so intravenous saline and pamidronate or oral prednisolone are often the practical options.

Monitoring. Corrected calcium daily; creatinine, phosphate, magnesium and potassium; ECG in severe disease; urine output and volume status.

Referral and escalation. Calcium over 3.5 mmol/L, confusion, AKI, arrhythmia, failure to respond within 3 days, or an unknown cause.

Comparison with alternative classes. Saline works fastest and is safe; bisphosphonates give lasting control; denosumab suits kidney failure; calcitonin is fast but short-lived; steroids target vitamin D-driven causes.