🦴 Abnormal Bone Profile — Assessment & Management

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 hospital treatment is IV 0.9% saline — rehydration promotes urinary calcium excretion — with assessment of cardiac and renal function and monitoring for fluid overload (Society for Endocrinology emergency guidance). Loop diuretics (furosemide) should not be used routinely to lower calcium — they are reserved for fluid overload after specialist assessment — older textbooks recommended furosemide to 'flush' calcium, but this increases dehydration and worsens the hypercalcaemia. After rehydration, an IV bisphosphonate (e.g. zoledronic acid) may be given in hospital, with renal-function and product-specific precautions. Denosumab for refractory malignancy-associated hypercalcaemia is an oncology/specialist treatment. PTHrP is not routinely required in primary care or in every patient with suppressed PTH — it is a specialist test when the cause remains unclear.

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 (repeat and trend; calcium, phosphate, vitamin D, PTH, renal function; radiography or specialist referral directed by symptoms and level) rather than hepatic investigation. Also consider recent fracture or surgery, pregnancy, renal disease and medications. 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), 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 — specialist imaging; a skeletal survey is not the preferred investigation). NICE NG12: offer FBC, calcium, ESR/plasma viscosity and protein electrophoresis + serum free light chains to people aged 60 and over with persistent bone pain (particularly back pain) or unexplained fracture; use a suspected cancer pathway if these tests suggest myeloma.

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 usually <0.01 (kidneys avidly reabsorb calcium because the calcium-sensing receptor mutation makes the kidney 'think' calcium is normal) — but values overlap, especially 0.01–0.02, and results can be falsely low with vitamin D deficiency, CKD, low calcium intake, thiazides, lithium or incomplete collection; inappropriate surgery is a recognised consequence of overinterpreting urinary calcium. 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 or equivocal urine calcium should prompt discussion with endocrinology/genetics (family history, CaSR mutation analysis) before any surgical decision.

Primary hyperparathyroidism surveillance without surgery is appropriate for asymptomatic patients who do not meet surgical criteria — NICE NG132 (2019) refers for surgery if there are symptoms of hypercalcaemia, end-organ disease (renal stones, fragility fracture or osteoporosis) or albumin-adjusted calcium 2.85 mmol/L or above; the international workshop criteria (international) add: serum calcium >0.25 mmol/L above ULN, 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: albumin-adjusted calcium and eGFR at least annually (ensure calcium remains stable, not rising), DXA every 2–3 years, and renal tract ultrasound if symptoms develop or a renal stone is suspected (NICE NG132). The surgeon's decision is based on a combination of risk factors and patient preference — NICE advises that referral can be considered even when surgical criteria are absent, so surveillance should be agreed with endocrinology rather than decided on age alone. 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 is commonly used, after checking renal function, calcium and vitamin D status. The Paget's Association-endorsed 2019 clinical guideline (Ralston et al., JBMR) recommends bisphosphonates for Paget's bone pain, with zoledronic acid the most likely to give a favourable pain response, and recommends symptom-directed treatment rather than treating to normalise ALP. 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 (1 g 6-hourly) or ibuprofen (400 mg 8-hourly, if no contraindication) for 24–48 hours 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 considered for IV zoledronic acid (once yearly — no oesophageal risk) or denosumab 60 mg SC every 6 months (which must not be stopped or delayed without an alternative antiresorptive plan).

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 (within cardiac and renal limits, 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.

Current NOGG 2024 guidance generally advises at least 5 years of oral bisphosphonate (longer for higher-risk patients) and review of IV zoledronate after 3 years; any treatment pause is individualised by age, prior hip/vertebral fracture, glucocorticoid use, new fractures, current BMD and overall fracture risk. The treatment review is a National Osteoporosis Guideline Group 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 is not based on T-score alone — it combines DXA reassessment with clinical risk factors and overall fracture risk. During any treatment pause, the patient should maintain adequate calcium and vitamin D intake (supplementing only where needed), weight-bearing exercise, fall prevention measures, and annual FRAX reassessment. Restart bisphosphonate if FRAX indicates high fracture risk during the holiday.