Hypercalcaemic crisis is a medical emergency — at serum calcium above 3.0–3.5 mmol/L, patients develop: nausea, vomiting (further dehydration worsening hypercalcaemia), polyuria (nephrogenic diabetes insipidus from calcium impairing renal concentrating ability), constipation, confusion (calcium impairs neuronal function), QT shortening on ECG (shortened ST segment — 'tombstone T-wave'). The initial treatment is aggressive IV fluid resuscitation (normal saline 200–300 ml/hour) — rehydration promotes urinary calcium excretion. Loop diuretics (furosemide) are NO LONGER recommended for acute hypercalcaemia unless oedema or fluid overload develops — older textbooks recommended furosemide to 'flush' calcium, but this increases dehydration and worsens the hypercalcaemia. After rehydration, IV zoledronic acid (4 mg over 15 minutes) is the most potent bisphosphonate for rapidly lowering calcium (calcium nadir at 48–72 hours). For malignancy-associated hypercalcaemia (PTHrP-mediated) not responding to bisphosphonate: denosumab 120 mg SC (anti-RANKL) is increasingly used. The PTHrP assay is the key diagnostic test distinguishing malignancy-associated hypercalcaemia (elevated PTHrP + suppressed PTH) from primary hyperparathyroidism (elevated PTH + normal/suppressed PTHrP).

The ALP isoform distinction is practically important because ALP can be elevated from liver, bone, or other sources, and the clinical significance and management differ completely. The quickest differentiator in primary care is GGT (gamma-glutamyl transferase) — GGT is elevated when ALP is of hepatic origin (cholestasis, hepatitis, alcohol, hepatic metastases) and is normal when ALP is of bone origin (Paget's, osteomalacia, bone metastases). A pattern of isolated elevated ALP with normal GGT, normal bilirubin, and normal transaminases points definitively to bone ALP — this should trigger bone investigation (X-ray for Paget's, vitamin D level for osteomalacia, bone scan for metastases) rather than hepatic investigation. If GGT is also elevated, hepatic investigation takes priority. Some laboratories offer formal ALP isoenzyme fractionation to distinguish bone vs liver ALP — request this if the GGT vs LFT pattern is inconclusive.

Myeloma is an important but frequently delayed diagnosis that GPs must consider in the context of hypercalcaemia — multiple myeloma causes hypercalcaemia through osteoclast activation (RANKL-mediated bone resorption by myeloma cells → calcium release), and the calcium is driven by osteolysis rather than PTH or PTHrP. The key diagnostic tests: serum protein electrophoresis (SPEP) showing a paraprotein band (M-protein), urine Bence Jones protein (free light chains — BJP), serum free light chain ratio (κ/λ ratio — very sensitive for light-chain myeloma), and bone marrow biopsy. The CRAB criteria for myeloma (requiring treatment): Calcium elevated, Renal impairment (creatinine >177 μmol/L), Anaemia (Hb <10g/dL), Bone lesions (lytic lesions on skeletal survey — standard MGUS/myeloma X-ray survey includes skull, spine, pelvis, femora, humeri). GPs should request SPEP + BJP + serum free light chains in any elderly patient with: unexplained hypercalcaemia + anaemia + elevated creatinine + bone pain.

Familial hypocalciuric hypercalcaemia (FHH) is the most important benign mimic of primary hyperparathyroidism — failure to diagnose FHH before parathyroid surgery results in unnecessary operations that do not correct the hypercalcaemia (because the mutation is in the calcium-sensing receptor, not the parathyroid glands). The diagnostic test: 24-hour urine calcium + creatinine to calculate the calcium-to-creatinine clearance ratio (CCCR). In primary hyperPTH: CCCR >0.02 (elevated urinary calcium from high filtered load). In FHH: CCCR <0.01 (kidneys avidly reabsorb calcium because the calcium-sensing receptor mutation makes the kidney 'think' calcium is normal). CCCR = (urine Ca × serum Cr) / (serum Ca × urine Cr). The 24-hour urine calcium should be checked before referring any patient with hypercalcaemia + mild/normal PTH for parathyroid surgery — a low urine calcium should trigger FHH testing (genetics, family history, CaSR mutation analysis) before any surgical referral.

Primary hyperparathyroidism surveillance without surgery is appropriate for asymptomatic patients who do not meet surgical criteria — the NICE and international consensus criteria for surgery are: serum calcium >0.25 mmol/L above ULN (approximately >2.85 mmol/L), age under 50, eGFR below 60, osteoporosis (T-score <-2.5 at any site or fragility fracture), 24h urine calcium >10 mmol/24h (nephrolithiasis risk), any symptomatic patient. Patients who do not meet these criteria can be monitored conservatively with: annual adjusted calcium (ensure remains stable, not rising), annual renal function + urinalysis (nephrocalcinosis), and 1–2 yearly DEXA (bone density monitoring). The surgeon's decision is based on a combination of risk factors and patient preference — many patients over 70 with mild asymptomatic primary hyperPTH are safely managed without surgery for years. However, over 10–15 years, approximately 30% of asymptomatic patients will develop an indication for surgery — the monitoring schedule allows timely identification.

Zoledronic acid for Paget's disease achieves the most sustained remission of any bisphosphonate — a single IV infusion of 5 mg zoledronic acid normalises ALP in approximately 90% of patients at 6 months, with remission maintained in approximately 60% of patients at 6 years. The NICE TA 2010 guidance supports zoledronic acid as first-line for symptomatic Paget's disease or when ALP is more than 3× the upper limit of normal. The acute phase reaction (flu-like symptoms 24–72 hours after the infusion: fever, myalgia, headache, fatigue) occurs in approximately 30% of patients receiving their first zoledronic acid infusion. Prophylactic paracetamol or ibuprofen 500–1000 mg 6-hourly for 24–48 hours significantly reduces this reaction. The reaction is mediated by γδ T-cell release of cytokines (pyrogenic) and is less severe with subsequent infusions. Dental review before zoledronic acid is important — osteonecrosis of the jaw (ONJ), while much rarer with single-dose Paget's treatment than with monthly high-dose oncological bisphosphonate regimens, remains a risk. Patients should have any necessary dental work completed before starting bisphosphonate therapy.

The alendronic acid oesophageal injury prevention instructions are one of the most important prescribing instructions in primary care — alendronic acid (and other oral bisphosphonates) are highly corrosive to oesophageal mucosa if they remain in contact with it. The safety rules are absolute: (1) take with a full glass (200 ml) of plain water (not juice, coffee, or mineral water — these reduce bioavailability + increase oesophageal exposure time); (2) take on an empty stomach, at least 30 minutes before any food or drink; (3) remain completely upright (sitting or standing — not reclining or lying down) for at least 30 minutes after taking the tablet. If these instructions are not followed, the tablet can lodge in the oesophagus, causing severe oesophageal ulceration, stricture, or perforation. GPs should ask about compliance with these instructions at every bisphosphonate prescription renewal. Patients who cannot comply (e.g., severe GORD, inability to stand) should be switched to IV zoledronic acid (once yearly — identical efficacy, no oesophageal risk) or denosumab SC every 6 months.

The calcium restriction paradox in primary hyperparathyroidism is counter-intuitive but important — GPs might instinctively advise patients with hypercalcaemia from primary hyperPTH to restrict dietary calcium. This is incorrect: calcium restriction in primary hyperPTH increases PTH secretion (the parathyroid adenoma is autonomous but still responds to a perceived low calcium signal by secreting more PTH), which then stimulates: (1) bone resorption (worsening osteoporosis), and (2) increased 1,25-OH-D production (worsening gut calcium absorption in the long run by stimulating vitamin D activation). The correct advice: maintain normal dietary calcium intake (700–1,000 mg/day from food, not supplements), ensure adequate hydration (2+ L/day to prevent renal stones), and avoid calcium supplements unless vitamin D deficiency is also present. Adequate hydration is the most important non-surgical intervention for preventing renal stones in primary hyperPTH — the most common complication of untreated primary hyperPTH.

The drug holiday from bisphosphonates at 5 years is a NICE recommendation that applies to alendronic acid and other oral bisphosphonates for osteoporosis — after 5 years of bisphosphonate use, bisphosphonate molecules accumulate in bone (half-life in bone approximately 10+ years) and the risk of atypical subtrochanteric or diaphyseal femoral fractures increases. The drug holiday (stopping bisphosphonate for 2–3 years) allows clearance of accumulated drug while residual bone benefit is maintained. The decision to take a drug holiday should be based on DEXA reassessment at 5 years: if T-score is above -2.5 (osteopenia range) and no new fragility fractures → drug holiday appropriate; if T-score remains below -2.5 or new fragility fracture → continue bisphosphonate (reassess again at 3 years). During the drug holiday, the patient should continue calcium + vitamin D supplementation, weight-bearing exercise, fall prevention measures, and annual FRAX reassessment. Restart bisphosphonate if FRAX indicates high fracture risk during the holiday.