Calcium, Phosphate & Bone Physiology

Calcium and phosphate homeostasis is governed by three principal hormones — parathyroid hormone (PTH), calcitriol (1,25-dihydroxycholecalciferol) and calcitonin — acting on three organs: bone, kidney and gut. This is a perennial NEET PG favourite because a single regulatory loop explains hypoparathyroidism, rickets, osteomalacia, renal osteodystrophy and Paget disease.

Calcium: distribution and physiological forms

The adult body contains roughly 1000–1200 g of calcium, of which 99% is in bone as hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂]. Only the remaining ~1% is in extracellular fluid and soft tissue, yet it is this tiny pool that is tightly regulated (normal serum total calcium 8.5–10.5 mg/dL or 2.1–2.6 mmol/L).

Serum calcium exists in three forms:

Form	Approx %	Physiologically active?	Notes
Ionised (free) Ca²⁺	~50%	Yes — the regulated fraction	Sensed by CaSR; ~4.6–5.3 mg/dL
Protein-bound (mainly albumin)	~40%	No	Falls in hypoalbuminaemia
Complexed (citrate, phosphate, bicarbonate)	~10%	No	Diffusible but inactive

High-yield: Correct total calcium for albumin → add 0.8 mg/dL of calcium for every 1 g/dL fall of albumin below 4 g/dL. This is why a malnourished patient may have "low" total calcium with normal ionised calcium and no symptoms.

Effect of pH on ionised calcium: alkalosis increases protein binding and lowers ionised Ca²⁺ → tetany (classic: hyperventilation → respiratory alkalosis → carpopedal spasm). Acidosis raises ionised calcium.

High-yield: Alkalosis → ↓ionised Ca²⁺ → tetany. Acidosis → ↑ionised Ca²⁺. Citrate in stored blood chelates calcium → hypocalcaemia after massive transfusion.

Phosphate physiology

Phosphate is the major intracellular anion; ~85% is in bone, the rest intracellular. Normal serum phosphate is 2.5–4.5 mg/dL (higher in children due to growth). Phosphate handling mirrors and opposes calcium: PTH is phosphaturic, and the bone-derived hormone FGF-23 (with cofactor Klotho) is the dominant phosphate-lowering hormone, also suppressing 1-alpha hydroxylase.

The three calcitropic hormones

Parathyroid hormone (PTH)

• Source: chief cells of the four parathyroid glands (derived from 3rd and 4th pharyngeal/branchial pouches — inferior glands from the 3rd pouch, an exam trap because they migrate further).
• Stimulus for secretion: low ionised calcium (the dominant trigger), also high phosphate (indirectly, by binding calcium and via FGF-23), and low calcitriol. Mild hypomagnesaemia stimulates PTH; severe hypomagnesaemia paradoxically inhibits PTH secretion and causes resistance — a classic cause of refractory hypocalcaemia.
• Net effect: raises serum calcium, lowers serum phosphate.

PTH actions, organ by organ:

1. Bone → activates osteoclastic resorption (indirectly, via RANK-L expression on osteoblasts) → releases Ca²⁺ and phosphate.
2. Kidney (distal tubule) → increases calcium reabsorption.
3. Kidney (proximal tubule) → inhibits phosphate reabsorption (phosphaturia) by internalising the NaPi-IIa cotransporter — this is why PTH lowers serum phosphate despite mobilising it from bone.
4. Kidney → stimulates 1-alpha hydroxylase, converting 25-OH-D to active 1,25-(OH)₂-D → indirectly boosts gut calcium absorption.

High-yield flow: ↓ionised Ca²⁺ → CaSR senses fall → ↑PTH → (bone resorption + distal renal Ca reabsorption + ↑calcitriol → gut Ca absorption) → serum Ca rises → CaSR feedback → PTH switched off.

High-yield: Continuous high PTH (hyperparathyroidism) is catabolic to bone, but intermittent PTH (teriparatide, given once daily) is anabolic — the basis of osteoporosis therapy.

Calcitriol (1,25-dihydroxycholecalciferol)

Vitamin D is a prohormone/steroid hormone activated in two hydroxylation steps:

Skin (7-dehydrocholesterol + UVB → cholecalciferol/D₃) → liver 25-hydroxylase → 25-OH-D (calcidiol, the storage form, best marker of status) → kidney 1-alpha hydroxylase → 1,25-(OH)₂-D (calcitriol, active form).

Metabolite	Site of formation	Significance
Cholecalciferol (D₃)	Skin / diet	Inactive precursor
25-OH-D (calcidiol)	Liver	Best index of vitamin D stores (long half-life)
1,25-(OH)₂-D (calcitriol)	Kidney (PCT)	Active hormone; short half-life
24,25-(OH)₂-D	Kidney	Inactive degradation product

Regulation of 1-alpha hydroxylase: stimulated by PTH, low phosphate, low calcium; inhibited by FGF-23, high phosphate, calcitriol itself (negative feedback).

Actions of calcitriol:

• Gut: ↑absorption of both calcium and phosphate (via calbindin) — the principal action.
• Bone: permits mineralisation; in excess, mobilises calcium.
• Kidney: minor ↑Ca reabsorption.
• Net: raises both serum calcium AND phosphate (contrast with PTH which lowers phosphate).

High-yield: Granulomatous diseases (sarcoidosis, tuberculosis, lymphoma) cause hypercalcaemia via extra-renal 1-alpha hydroxylase in macrophages → unregulated calcitriol. PTH is suppressed.

Calcitonin

• Source: parafollicular C cells of the thyroid (neural crest origin).
• Stimulus: high serum calcium.
• Action: inhibits osteoclastic bone resorption → lowers calcium. Largely a weak/minor hormone in humans — thyroidectomy does not cause hypercalcaemia.
• Clinical use: tumour marker for medullary thyroid carcinoma; therapy in acute hypercalcaemia, Paget disease, and osteoporosis (with rapid but transient effect).

Feature	PTH	Calcitriol	Calcitonin
Source	Chief cells (parathyroid)	Kidney (final step)	C cells (thyroid)
Trigger	↓ Ca²⁺	↑PTH, ↓Ca, ↓PO₄	↑ Ca²⁺
Serum calcium	↑	↑	↓
Serum phosphate	↓ (phosphaturic)	↑	↓
Receptor	GPCR (Gs)	Nuclear (VDR)	GPCR

The calcium-sensing receptor (CaSR)

A G-protein-coupled receptor on parathyroid chief cells and the renal tubule (thick ascending limb). It is the "thermostat" — when ionised Ca²⁺ rises, CaSR is activated and inhibits PTH secretion; when Ca²⁺ falls, CaSR is silent and PTH is released.

High-yield CaSR genetics:

• Inactivating mutation → gland thinks calcium is low → ↑PTH, ↑Ca → Familial Hypocalciuric Hypercalcaemia (FHH): mild hypercalcaemia with low urinary calcium and inappropriately normal/high PTH. Key DDx of primary hyperparathyroidism (urine Ca/creatinine clearance ratio < 0.01 in FHH). Parathyroidectomy does NOT help — do not operate.
• Activating mutation → gland thinks calcium is high → ↓PTH → Autosomal Dominant Hypocalcaemia.
• Cinacalcet is a calcimimetic (activates CaSR) used in secondary/tertiary hyperparathyroidism and parathyroid carcinoma.

Clinical correlation: hypocalcaemia and hypoparathyroidism

Features of hypocalcaemia (increased neuromuscular excitability):

• Chvostek sign — tapping the facial nerve anterior to the ear → ipsilateral facial twitch.
• Trousseau sign — BP cuff inflated above systolic for 3 min → carpopedal spasm (more specific).
• Perioral paraesthesia, tetany, laryngospasm, seizures, prolonged QT interval on ECG.

Causes of hypoparathyroidism:

• Post-surgical (commonest — after thyroidectomy/parathyroidectomy).
• DiGeorge syndrome — 22q11 deletion, failure of 3rd & 4th pharyngeal pouch development → absent parathyroids + thymic aplasia (the classic CATCH-22).
• Autoimmune (APS-1/APECED).
• Severe hypomagnesaemia.

Pseudohypoparathyroidism (Albright hereditary osteodystrophy): end-organ resistance to PTH due to Gsα (GNAS) defect → low calcium, high phosphate, but HIGH PTH. Phenotype: short stature, round face, short 4th and 5th metacarpals, obesity. Pseudopseudohypoparathyroidism = same phenotype with normal biochemistry.

Disorder	Ca	PO₄	PTH
Primary hypoparathyroidism	↓	↑	↓
Pseudohypoparathyroidism	↓	↑	↑
Vitamin D deficiency	↓	↓	↑ (secondary)
Primary hyperparathyroidism	↑	↓	↑
FHH	↑	normal/↓	normal/↑
Humoral hypercalcaemia of malignancy (PTHrP)	↑	↓	↓ (PTH), PTHrP ↑

High-yield: Memory aid for primary hyperparathyroidism — "stones, bones, abdominal groans, psychic moans" (renal calculi, osteitis fibrosa cystica, peptic ulcer/pancreatitis, depression). Commonest cause = solitary parathyroid adenoma.

Rickets versus osteomalacia

Both result from defective mineralisation of osteoid (usually vitamin D deficiency); rickets affects the growing skeleton (open epiphyseal plates) in children, osteomalacia the mature skeleton in adults.

Feature	Rickets	Osteomalacia
Age	Children (growth plates open)	Adults
Bone affected	Growth plate + osteoid	Osteoid only
Signs	Bow legs/knock knees, rachitic rosary, frontal bossing, widened wrists, Harrison sulcus, craniotabes	Bone pain, proximal myopathy, waddling gait
X-ray	Cupping, fraying, splaying of metaphyses	Looser zones (pseudofractures) in pubic rami, femoral neck, scapula
Biochemistry (typical)	↓Ca, ↓PO₄, ↑ALP, ↑PTH, ↓25-OH-D	Same

High-yield: Looser zones (Milkman pseudofractures) are pathognomonic of osteomalacia. Alkaline phosphatase is raised in rickets/osteomalacia (osteoblast activity) — a key discriminator from disorders with normal ALP.

Vitamin-D-resistant rickets:

• X-linked hypophosphataemic rickets — commonest inherited form; PHEX mutation → ↑FGF-23 → renal phosphate wasting → low phosphate, normal calcium, normal/low calcitriol. Treat with phosphate + calcitriol; burosumab (anti-FGF-23) is the modern agent.
• Type 1 (vitamin-D-dependent) rickets — 1-alpha hydroxylase deficiency → low calcitriol; treat with calcitriol.
• Type 2 — defective vitamin D receptor; high calcitriol, alopecia.

Paget disease of bone (osteitis deformans)

A disorder of disordered, accelerated bone remodelling — excessive osteoclastic resorption followed by chaotic, disorganised osteoblastic new bone (woven, mechanically weak "mosaic/jigsaw" pattern). Aetiology is multifactorial (possible paramyxovirus inclusions in osteoclasts; SQSTM1 mutations).

Stages: osteolytic → mixed → osteosclerotic ("burnt-out").

Clinical: often asymptomatic; bone pain, enlarging skull (increasing hat size), bowing of tibia (sabre tibia), deafness (CN VIII compression / ossicle involvement), high-output cardiac failure (hypervascular bone), pathological fractures.

Biochemistry: markedly raised alkaline phosphatase with NORMAL calcium and phosphate — the classic pattern. (Calcium may rise only with immobilisation.) Urinary hydroxyproline raised.

Investigation of choice: radionuclide bone scan for extent; X-ray for diagnosis (cotton-wool skull, V-shaped lytic front "blade of grass", cortical thickening).

High-yield: Paget = isolated very high ALP with normal Ca/PO₄. Most feared complication is osteosarcoma (sudden ↑pain/swelling). Drug of choice = bisphosphonates (zoledronate).

Investigations: the diagnostic approach

Stepwise workup of an abnormal calcium:

1. Confirm with ionised calcium / albumin-corrected calcium.
2. Measure intact PTH — the single most useful test.
   • High Ca + high/inappropriately normal PTH → primary hyperparathyroidism or FHH (check urine calcium).
   • High Ca + suppressed PTH → malignancy (measure PTHrP), vitamin D excess, granulomatous disease.
   • Low Ca + low PTH → hypoparathyroidism.
   • Low Ca + high PTH → vitamin D deficiency / CKD / pseudohypoparathyroidism.
3. 25-OH-D for vitamin D status; phosphate, ALP, magnesium, creatinine complete the panel.

Management / drugs of choice

• Acute symptomatic hypocalcaemia: IV calcium gluconate (10% — preferred peripherally; calcium chloride is more irritant). Correct magnesium if low.
• Chronic hypoparathyroidism: oral calcium + active vitamin D (calcitriol/alfacalcidol); recombinant PTH in refractory cases.
• Acute severe hypercalcaemia: IV normal saline (rehydration first) → then IV bisphosphonate (zoledronate); calcitonin for rapid but transient effect; denosumab if bisphosphonate-refractory; glucocorticoids for vitamin-D-mediated/granulomatous hypercalcaemia.
• Primary hyperparathyroidism: parathyroidectomy is curative (definitive).
• Osteoporosis: bisphosphonates first-line; teriparatide (anabolic, intermittent PTH); denosumab (anti-RANKL).
• Rickets/osteomalacia: vitamin D + calcium repletion.

Complications snapshot

• Hypocalcaemia → tetany, laryngospasm, seizures, prolonged QT, cataract & basal ganglia calcification in chronic hypoparathyroidism.
• Hypercalcaemia → nephrolithiasis, nephrocalcinosis, short QT, constipation, pancreatitis, "moans & groans," coma.
• Chronic hyperphosphataemia (CKD) → secondary/tertiary hyperparathyroidism, renal osteodystrophy, vascular calcification.

Recently asked / exam angle

• Albumin correction formula and the alkalosis → low ionised calcium → tetany link are repeatedly tested in physiology/biochemistry MCQs.
• Single-best-answer pattern: a table of Ca/PO₄/PTH/ALP asking you to name the disorder (memorise the comparison table above).
• FHH vs primary hyperparathyroidism distinguished by urinary calcium (low in FHH; Ca/Cr clearance ratio < 0.01) — high-yield surgery/medicine overlap.
• Pseudohypoparathyroidism = low Ca, high PO₄, high PTH (resistance) — a classic distractor against hypoparathyroidism.
• Best marker of vitamin D status = 25-OH-D, while the active form = 1,25-(OH)₂-D (1-alpha hydroxylated in kidney).
• Paget disease = isolated raised ALP, normal calcium; bone scan for extent; osteosarcoma is the dreaded complication.
• Inferior parathyroids from the 3rd pharyngeal pouch, DiGeorge from 22q11 (3rd & 4th pouch) — embryology cross-link.
• PTH is phosphaturic while calcitriol raises phosphate — direction of phosphate change is a favourite discriminator.
• Mechanism of continuous vs intermittent PTH (teriparatide anabolic) and calcimimetic cinacalcet activating CaSR.

Rapid revision

1. Ionised calcium (~50%) is the regulated, active fraction; correct total Ca by +0.8 mg/dL per 1 g/dL fall in albumin.
2. PTH raises calcium and LOWERS phosphate (phosphaturic); calcitriol raises both.
3. PTH stimulates renal 1-alpha hydroxylase → activates vitamin D; FGF-23 suppresses it and wastes phosphate.
4. 25-OH-D = best status marker; 1,25-(OH)₂-D = active hormone.
5. CaSR inactivating mutation → FHH (high Ca, low urine Ca, don't operate); activating → autosomal dominant hypocalcaemia.
6. Alkalosis → ↓ionised Ca → tetany; Trousseau (carpopedal spasm) more specific than Chvostek.
7. Pseudohypoparathyroidism: low Ca, high PO₄, HIGH PTH (Gsα/GNAS resistance, short 4th–5th metacarpals).
8. Rickets/osteomalacia: ↓Ca, ↓PO₄, ↑ALP, ↑PTH; Looser zones in osteomalacia, metaphyseal cupping/fraying in rickets.
9. X-linked hypophosphataemic rickets: PHEX → ↑FGF-23 → phosphate wasting; treat with burosumab.
10. Paget disease: isolated very high ALP, normal Ca/PO₄; bisphosphonates DOC; osteosarcoma feared.
11. Calcitonin (C cells, ↑Ca trigger) lowers calcium — minor in humans; marker for medullary thyroid carcinoma.
12. Primary hyperparathyroidism: adenoma, "stones/bones/groans/moans," ↑Ca ↓PO₄ ↑PTH; parathyroidectomy curative; saline + zoledronate for acute hypercalcaemia.