38 CALCIUM & BONE DISEASE

# 39 CALCIUM & BONE DISEASE

Calcium is one of the most tightly regulated ions in the body. The plasma calcium concentration is held within roughly 2.2–2.6 mmol/L because even small deviations disrupt neuromuscular excitability, cardiac contractility and coagulation. The MRCS examiners love this topic because a handful of hormones, three glands and a few characteristic biochemical patterns can be recombined into dozens of SBA questions. Master the patterns and the lesson collapses into pure pattern recognition.

Calcium homeostasis

Three hormones do almost all the work: parathyroid hormone (PTH), calcitriol (the active form of vitamin D) and calcitonin.

[Image: Calcium homeostasis diagram — PTH/Vit D/calcitonin actions on bone, gut, kidney]

Parathyroid hormone

PTH is a peptide hormone secreted by the chief cells of the four parathyroid glands. Its release is triggered directly by low ionised calcium acting on the calcium-sensing receptor (CaSR) — it is not under anterior pituitary control. PTH raises serum calcium by three mechanisms:

➡ Bone — stimulates osteoclastic resorption (indirectly, via RANKL on osteoblasts) releasing Ca²⁺ and phosphate

➡ Kidney — increases Ca²⁺ reabsorption in the distal convoluted tubule and decreases phosphate reabsorption in the proximal tubule

➡ Kidney (indirect on gut) — activates 1α-hydroxylase in the proximal tubule, converting 25-(OH) vitamin D into calcitriol (1,25-(OH)₂ vitamin D), which then increases gut absorption of calcium and phosphate

The net effect is calcium up, phosphate down. The phosphate-lowering effect is a key fingerprint — if PTH is high but phosphate is also high, something else is going on (renal failure, tertiary disease, or PTH resistance).

👩‍⚕️ PTH does NOT act directly on the gut. Gut calcium absorption is mediated entirely by calcitriol. This is a classic SBA trap.

Calcitriol (active vitamin D)

Cholecalciferol (D3) is made in skin from 7-dehydrocholesterol under UVB, or absorbed from diet. The liver adds a 25-OH group; the kidney adds a 1-OH group under PTH control to produce calcitriol. Calcitriol raises both calcium and phosphate by increasing gut absorption — the only hormone that does so.

Calcitonin

Secreted by the parafollicular (C) cells of the thyroid, calcitonin lowers calcium by inhibiting osteoclasts. Its physiological role in humans is minor (thyroidectomy does not cause hypocalcaemia), but it has two exam hooks: it is the tumour marker for medullary thyroid carcinoma, and C cells are derived from the ultimobranchial body (4th/5th pharyngeal pouch).

Hyperparathyroidism

	Primary	Secondary	Tertiary
Cause	Parathyroid adenoma (80%), hyperplasia (15%), carcinoma (1%)	CKD or vit D deficiency → low Ca²⁺ drives PTH	Long-standing secondary → autonomous gland
Calcium	↑	↓ or normal	↑
Phosphate	↓	↑ (in CKD)	↑
PTH	↑	↑	↑↑
ALP	↑	↑	↑
Classic patient	Postmenopausal woman, "stones, bones, groans, psychic moans"	CKD patient	Renal transplant recipient with persistent ↑Ca

👩‍⚕️ Three-line shortcut: Ca up + PTH up + phosphate down = primary. Ca down + PTH up + phosphate up = secondary (CKD). Ca up + PTH up + phosphate up = tertiary.

Primary hyperparathyroidism

Almost always a solitary adenoma. Hypercalcaemia causes the classic tetrad: renal stones, bone pain (osteitis fibrosa cystica with brown tumours in severe disease), abdominal groans (constipation, peptic ulcer, pancreatitis) and psychic moans (depression, confusion). Localise with technetium-99m sestamibi scan (sensitive and specific), often combined with neck ultrasound. CT/MRI are second-line for re-operative or ectopic cases. Acute hypercalcaemia is treated first with aggressive IV fluid resuscitation, then bisphosphonates; definitive treatment is parathyroidectomy.

Secondary hyperparathyroidism

The parathyroids are doing their job appropriately in response to a stimulus. In CKD, failing kidneys cannot excrete phosphate (so phosphate rises) and cannot 1α-hydroxylate vitamin D (so calcitriol falls and gut calcium absorption drops). Low calcium and high phosphate both drive PTH up. Calcium is low or normal — never high.

Tertiary hyperparathyroidism

After years of secondary stimulation, the parathyroids become hyperplastic and autonomous. They keep pumping out PTH even after the original stimulus (CKD) is corrected — classically after renal transplantation. Calcium now rises because the autonomous gland no longer responds to feedback. Treatment is surgical (subtotal or total parathyroidectomy with autotransplantation).

Hypoparathyroidism and PTH resistance

➡ Post-surgical — the commonest cause; inadvertent removal or devascularisation during total thyroidectomy

➡ DiGeorge syndrome — failure of the 3rd and 4th pharyngeal pouches; absent parathyroids and thymus, cardiac anomalies, characteristic facies (CATCH-22)

➡ Autoimmune — isolated or part of APS type 1

Hypocalcaemia causes neuromuscular hyperexcitability: perioral paraesthesia, carpopedal spasm, Chvostek's sign (facial twitch on tapping the facial nerve) and Trousseau's sign (carpal spasm on inflating a BP cuff). ECG shows a prolonged QT.

Pseudohypoparathyroidism (Albright's hereditary osteodystrophy) is end-organ resistance to PTH due to a defective Gs-alpha subunit. PTH is high but tissues cannot respond, so calcium is low and phosphate is high. Patients have short stature, short fourth and fifth metacarpals, and a round face. Pseudo-pseudohypoparathyroidism has the same phenotype but normal biochemistry.

Metabolic bone disease

[Image: Comparison chart — Ca, PO4, ALP, PTH in osteoporosis, osteomalacia, Paget's, primary/secondary/tertiary hyperPTH, metastases]

Osteoporosis

Reduced bone mass with normal mineralisation. The microarchitecture is disrupted but the bone that remains is chemically normal — so calcium, phosphate, ALP and PTH are all normal. Diagnosed on DEXA scan: T-score ≤ −2.5 = osteoporosis, −1 to −2.5 = osteopenia. Risk factors: postmenopausal oestrogen loss, long-term steroids, hyperthyroidism, low BMI, smoking, alcohol. Treatment: bisphosphonates, calcium/vitamin D, denosumab (RANKL inhibitor).

Osteomalacia and rickets

Defective mineralisation of osteoid, almost always from vitamin D deficiency (dietary lack, malabsorption from Crohn's/coeliac, CKD, lack of sunlight). Low calcium absorption → secondary rise in PTH → phosphate wasting → low phosphate. ALP is high (osteoblasts working overtime to mineralise). Classic radiological feature: Looser's zones (pseudofractures). In children before growth-plate closure the same process is called rickets — bowing of long bones, frontal bossing, rachitic rosary.

👩‍⚕️ The Crohn's patient with low Ca, low PO₄ and high ALP is osteomalacia from fat-soluble vitamin malabsorption. This SBA appears every cycle.

Paget's disease of bone

Disordered bone remodelling — wildly increased osteoclastic resorption followed by chaotic osteoblastic deposition produces structurally weak, mosaic-pattern bone. Affects pelvis, skull, femur, tibia, vertebrae. Calcium and phosphate are normal; ALP is markedly elevated in isolation.

➡ Sabre tibia (anterior bowing)

➡ Enlarged skull, frontal bossing — hats don't fit any more

➡ Conductive and sensorineural deafness from skull base involvement compressing CN VIII

➡ High-output cardiac failure from hypervascular bone acting as an AV shunt

➡ Risk of osteosarcoma (1%) in long-standing disease

Treatment: bisphosphonates.

Osteopetrosis ("marble bone disease")

Defective osteoclast function (carbonic anhydrase II deficiency or RANKL pathway mutation). Bones are dense and sclerotic on X-ray but paradoxically brittle and fracture easily. Marrow space is obliterated → pancytopenia, extramedullary haematopoiesis, hepatosplenomegaly.

Hypercalcaemia of malignancy

Two mechanisms to keep distinct:

➡ PTHrP secretion — classically squamous cell carcinoma of the lung, also head and neck, renal, bladder, breast. PTHrP mimics PTH (↑Ca, ↓PO₄) but PTH itself is suppressed.

➡ Osteolytic metastases — breast, prostate, myeloma, lung. ↑Ca, ↑PO₄, ↑ALP (in osteoblastic mets), suppressed PTH.

Sarcoidosis and granulomatous hypercalcaemia

Macrophages within non-caseating granulomas express 1α-hydroxylase independent of renal/PTH control, generating calcitriol from circulating 25-(OH)D. Result: ↑Ca, ↑1,25-(OH)₂D, suppressed PTH, often with hypercalciuria (more common than overt hypercalcaemia) and nephrocalcinosis. Treat with steroids, which suppress macrophage 1α-hydroxylase. The same mechanism operates in TB, lymphoma and berylliosis.

Milk-alkali syndrome

Triad of hypercalcaemia, metabolic alkalosis and acute kidney injury from excess intake of calcium-containing antacids (or, historically, milk for peptic ulcer). PTH is suppressed. Resolves on stopping the offending agent — does not respond to steroids (unlike sarcoid).

MEN syndromes

Worth knowing cold for the exam.

	MEN 1	MEN 2A	MEN 2B
Gene	MEN1 (menin)	RET	RET
Parathyroid	✔ hyperplasia	✔	✘
Pituitary	✔ adenoma	✘	✘
Pancreas	✔ gastrinoma, insulinoma	✘	✘
Medullary thyroid Ca	✘	✔	✔
Phaeochromocytoma	✘	✔	✔
Mucosal neuromas / marfanoid	✘	✘	✔

Mnemonic: MEN 1 = 3 P's (Parathyroid, Pituitary, Pancreas). MEN 2A = 2 P's + Medullary (Parathyroid, Phaeo, Medullary). MEN 2B = MEN 2A minus parathyroid, plus Mucosal neuromas and Marfanoid habitus.

[Image: MCQs banner]

Test yourself

What is the histological appearance of osteoporosis?

• ((Normal mineralisation, reduced bone volume::☑️ Osteoid is reduced; the bone that remains is chemically normal.))
• ((Increased osteoclastic activity with woven bone::Describes Paget's disease, not osteoporosis.))
• ((Unmineralised osteoid seams::Describes osteomalacia — defective mineralisation.))
• ((Dense sclerotic bone with no marrow space::Describes osteopetrosis.))

👩‍⚕️ Osteoporosis biochemistry is entirely normal — diagnosis is on DEXA, not bloods.

A 50-year-old woman sustains a long bone fracture. Calcium is low, phosphate low, ALP high. Diagnosis?

• ((Osteomalacia::☑️ Vit D deficiency → low Ca, secondary phosphate wasting, high ALP from osteoblast drive.))
• ((Osteoporosis::Bloods would all be normal.))
• ((Paget's disease::Ca and PO₄ normal, isolated high ALP.))
• ((Primary hyperparathyroidism::Calcium would be high, not low.))

A patient with Crohn's disease has low calcium, low phosphate and high ALP. Diagnosis?

• ((Osteomalacia::☑️ Fat-soluble vitamin D malabsorption from terminal ileal disease.))
• ((Secondary hyperparathyroidism in CKD::Phosphate would be high.))
• ((Coeliac-related osteoporosis::Bloods would be normal in pure osteoporosis.))
• ((Paget's disease::Ca and PO₄ are normal in Paget's.))

A 60-year-old woman has back pain, has lost 8 cm in height over 5 years. Calcium high, phosphate normal, eGFR normal, PTH high. Diagnosis?

• ((Primary hyperparathyroidism::☑️ High Ca with inappropriately high PTH and no kidney disease.))
• ((Secondary hyperparathyroidism::Calcium would be low or normal, not high.))
• ((Tertiary hyperparathyroidism::Requires antecedent CKD or transplant history.))
• ((Osteoporosis::PTH and calcium would be normal.))
• ((Hypoparathyroidism::Calcium would be low.))

A 40-year-old woman has renal stones and a calcium of 3.8 mmol/L. Most likely cause?

• ((Solitary parathyroid adenoma::☑️ 80% of primary hyperparathyroidism; classic stones + severe hypercalcaemia.))
• ((Diffuse parathyroid hyperplasia::Accounts for ~15%; usually less dramatic.))
• ((Sarcoidosis::Rarely causes Ca this high or stones as the primary feature.))
• ((Idiopathic hypercalciuria::Calcium is normal by definition.))

Best imaging to localise a parathyroid adenoma?

• ((Technetium-99m sestamibi scan::☑️ Hyperfunctioning tissue shows delayed washout of tracer.))
• ((Ultrasound::Useful adjunct but lower sensitivity, especially for ectopic glands.))
• ((CT::Reserved for re-operative or ectopic cases.))
• ((MRI::Second-line, used when sestamibi/US inconclusive.))

👩‍⚕️ Localisation is for surgical planning — acute management of severe hypercalcaemia is IV fluids first.

A 56-year-old with back pain has high calcium, high phosphate, high ALP. Diagnosis?

• ((Metastatic bone disease::☑️ Lytic + osteoblastic mets release Ca and PO₄; ALP up from osteoblast activity.))
• ((Paget's disease::Ca and PO₄ are normal — isolated ALP rise.))
• ((Tertiary hyperparathyroidism::PO₄ pattern can overlap but PTH would be markedly elevated.))
• ((Osteomalacia::Ca and PO₄ would both be low.))
• ((Secondary hyperparathyroidism::Calcium would be low/normal.))

A renal transplant patient has recurrent bone pain, fractures, high calcium, low phosphate, high ALP. Diagnosis?

• ((Tertiary hyperparathyroidism::☑️ Autonomous parathyroid hyperplasia after long-standing secondary disease.))
• ((Primary hyperparathyroidism::Adenoma in a fresh transplant patient is far less likely than tertiary.))
• ((Secondary hyperparathyroidism::Calcium would not be high.))
• ((Hypoparathyroidism::Calcium would be low.))

An elderly woman with chronic back pain has high corrected calcium, phosphate at upper limit of normal, high PTH and low eGFR. Diagnosis?

• ((Tertiary hyperparathyroidism::☑️ High Ca + high PTH + CKD = autonomous parathyroid.))
• ((Primary hyperparathyroidism::Possible but the CKD context points to tertiary.))
• ((Secondary hyperparathyroidism::Calcium would be low or normal.))
• ((Pseudohypoparathyroidism::Calcium would be low.))

A 29-year-old with polyuria, recent rash, hilar shadowing on CXR, high calcium, high phosphate, normal ALP. After saline and hydrocortisone the calcium normalises and PTH is low. Diagnosis?

• ((Sarcoidosis::☑️ Granuloma macrophages express 1α-hydroxylase → calcitriol → ↑Ca with suppressed PTH; steroid responsive.))
• ((Carcinoma of the lung::PTHrP-mediated hypercalcaemia would not resolve with hydrocortisone.))
• ((Familial hypocalciuric hypercalcaemia::Lifelong, asymptomatic, low urine Ca.))
• ((Secondary hyperparathyroidism::PTH would be high.))

A patient is depressed and has abdominal pain, with hypercalcaemia, normal phosphate, normal PTH. Calcium normalises after prednisolone. Diagnosis?

• ((Sarcoidosis::☑️ Steroid-responsive granulomatous hypercalcaemia.))
• ((Milk-alkali syndrome::Caused by Ca antacids; not steroid-responsive.))
• ((Hypoparathyroidism::Causes low calcium, not high.))
• ((Sjögren's::Does not typically cause hypercalcaemia.))

A 33-year-old with depression and abdominal pain has low TSH and high calcium. Most likely diagnosis?

• ((Hyperparathyroidism::☑️ "Bones, stones, groans, psychic moans"; coexistent thyroid disease can confuse.))
• ((Hyperthyroidism::Can mildly raise Ca but not enough to explain psychiatric symptoms.))
• ((Milk-alkali syndrome::Would expect antacid history and metabolic alkalosis.))
• ((Vitamin D toxicity::Possible but rarer; PTH would be suppressed.))

A patient develops psychosis, hypercalcaemia and low TSH. Stopping a medication resolves everything. Diagnosis?

• ((Milk-alkali syndrome::☑️ Calcium-containing antacids (eg long-term Gaviscon/Tums) → ↑Ca, alkalosis, AKI.))
• ((Vitamin D toxicity::Possible but slower to resolve than days.))
• ((Hyperthyroidism::Would not produce isolated hypercalcaemia of this pattern.))
• ((Sarcoidosis::Would not resolve simply by stopping a drug.))

A 50-year-old smoker with lung mass, polyuria and high calcium. Most informative investigation?

• ((Parathyroid hormone-related peptide (PTHrP)::☑️ SCC of lung secretes PTHrP, mimicking PTH; PTH itself is suppressed.))
• ((PTH::Will be suppressed — confirms non-PTH cause but doesn't identify it.))
• ((1,25-dihydroxycholecalciferol::Elevated in granulomatous disease, not paraneoplastic.))
• ((ACTH::Relevant for Cushing's/ectopic ACTH syndromes, not hypercalcaemia.))

A 45-year-old smoker with right upper lobe mass and corrected calcium 3.52 mmol/L. Most informative assay?

• ((Parathyroid hormone-related peptide (PTHrP)::☑️ Squamous cell lung Ca classically secretes PTHrP.))
• ((1,25-dihydroxycholecalciferol::Elevated in sarcoid/lymphoma, not lung SCC.))
• ((25-hydroxycholecalciferol::Storage form; useful for deficiency not malignancy.))
• ((PTH::Will be suppressed but doesn't pinpoint the mechanism.))
• ((Glucose::Irrelevant.))

Which electrolyte disturbance causes perioral tingling and muscle twitching after thyroidectomy?

• ((Hypocalcaemia::☑️ Inadvertent parathyroid injury → tetany, Chvostek, Trousseau, prolonged QT.))
• ((Hypercalcaemia::Fatigue and polyuria, not tetany.))
• ((Hyponatraemia::Confusion and seizures, not perioral spasm.))
• ((Hyperkalaemia::Weakness and cardiac changes.))
• ((Hypokalaemia::Cramps and arrhythmias, not perioral twitching.))

Which statement best describes parathyroid hormone?

• ((Accelerates renal hydroxylation of vitamin D::☑️ PTH activates 1α-hydroxylase in the proximal tubule.))
• ((Directly accelerates intestinal calcium absorption::Indirect — via calcitriol, not PTH itself.))
• ((Raises plasma phosphate::PTH causes phosphate excretion; phosphate falls.))
• ((Is a steroid hormone::PTH is a peptide hormone.))
• ((Is secreted under anterior pituitary control::Secretion is controlled by the calcium-sensing receptor.))

Revision summary

➡ PTH raises Ca, lowers PO₄. Acts on bone (resorption), kidney (Ca reabsorption, PO₄ excretion, 1α-hydroxylation) and gut (indirect via calcitriol)

➡ Calcitriol is the only hormone raising both Ca and PO₄

➡ Calcitonin (C cells of thyroid) — minor role; tumour marker for medullary thyroid Ca

➡ Primary hyperPTH: ↑Ca ↑PTH ↓PO₄ — adenoma 80%, localise with sestamibi

➡ Secondary hyperPTH: ↓/normal Ca ↑PTH ↑PO₄ — CKD

➡ Tertiary hyperPTH: ↑Ca ↑PTH ↑PO₄ — autonomous gland after transplant

➡ Osteoporosis: all bloods normal; DEXA T-score ≤ −2.5

➡ Osteomalacia: ↓Ca ↓PO₄ ↑ALP, Looser's zones, vit D deficiency

➡ Paget's: isolated ↑ALP; sabre tibia, deafness, high-output cardiac failure, osteosarcoma risk

➡ Malignancy: PTHrP (lung SCC, suppressed PTH) or osteolytic mets

➡ Sarcoidosis: granuloma 1α-hydroxylase → ↑calcitriol → ↑Ca, suppressed PTH; steroid-responsive

➡ Milk-alkali: ↑Ca + metabolic alkalosis + AKI from Ca-containing antacids

➡ Post-thyroidectomy hypocalcaemia: perioral tingling, Chvostek, Trousseau, prolonged QT

➡ MEN 1 = 3 P's (Parathyroid, Pituitary, Pancreas); MEN 2A = parathyroid + medullary + phaeo; MEN 2B = medullary + phaeo + mucosal neuromas (no parathyroid)