Calcium and bone physiology
Calcium and bone: PTH, vitamin D, calcitonin, hyper- and hypocalcaemia, bone drugs
PTH raises calcium and lowers phosphate; vitamin D raises both; calcitonin from C cells is a medullary carcinoma marker. Covers vitamin D metabolism, biochemical patterns, PTHrP, sarcoidosis, CKD bone disease, bisphosphonates and teriparatide.
The core idea
Plasma ionised calcium is held within narrow limits because nerves, muscle and the heart depend on it. Three hormones control the flows between gut, bone and kidney: PTH acts within minutes on bone and kidney; calcitriol acts over days on the gut; calcitonin has only a minor role in humans. Read calcium, phosphate, PTH and alkaline phosphatase together and most diagnoses follow.
Parathyroid hormone
- Made by chief cells of four parathyroid glands: the superior pair from the fourth pharyngeal pouch and the inferior pair from the third (they descend with the thymus). Both pairs are usually supplied by the inferior thyroid artery. Accidental removal or devascularisation at thyroidectomy is the commonest cause of hypoparathyroidism; DiGeorge syndrome is a congenital cause.
- The calcium-sensing receptor on chief cells reduces PTH when ionised calcium rises. Magnesium is needed for PTH release and action.
- Bone: PTH binds receptors on osteoblasts, which express RANKL; RANKL activates osteoclast precursors, releasing calcium and phosphate. Continuous high PTH causes net resorption; intermittent daily doses (teriparatide, an agonist) stimulate osteoblasts more than osteoclasts and build bone, even after bisphosphonate failure.
- Kidney: increases Ca²⁺ reabsorption in the distal tubule; blocks phosphate reabsorption in the proximal tubule; stimulates 1α-hydroxylase; reduces bicarbonate reabsorption.
- Net: calcium up, phosphate down.
Vitamin D
1. Skin: 7-dehydrocholesterol with UVB gives cholecalciferol (D₃); diet gives D₂ and D₃. 2. Liver: 25-hydroxylation to 25-hydroxyvitamin D, the storage and circulating form, measured to assess status. 3. Kidney (proximal tubule): 1α-hydroxylation to 1,25-dihydroxyvitamin D (calcitriol), the active hormone. Stimulated by PTH, low phosphate and low calcium; inhibited by FGF23, high phosphate and calcitriol itself. 4. When calcium is high (for example after a calcium load), PTH falls and the kidney switches to 24-hydroxylase, making the inactive 24,25-dihydroxycholecalciferol instead.
- Actions: raises intestinal absorption of both calcium and phosphate. In enterocytes calcitriol acts on a nuclear receptor to increase TRPV6 calcium channels and calbindin, so absorption rises over days. It promotes bone mineralisation and feeds back to inhibit PTH.
- Enzyme-inducing anticonvulsants (phenytoin, carbamazepine, phenobarbital) speed hepatic breakdown of vitamin D to inactive metabolites, causing osteomalacia even with sun exposure. Valproate and levetiracetam are not inducers.
- Granulomas (sarcoidosis, TB) contain unregulated macrophage 1α-hydroxylase, so calcitriol rises and causes hypercalcaemia with suppressed PTH; prednisolone inhibits this enzyme and treats the cause.
- Deficiency: rickets in children (bowed legs, widened wrists, rachitic rosary, delayed fontanelle closure) and osteomalacia in adults (bone pain, waddling gait, proximal weakness, Looser zones). Calcium low or normal, phosphate low, ALP high, PTH high.
Calcitonin
From parafollicular (C) cells of the thyroid (neural crest, ultimobranchial body). Lowers calcium by inhibiting osteoclasts. Little role in normal balance (thyroidectomy does not disturb calcium through calcitonin loss), but it is the tumour marker for medullary thyroid carcinoma, which shows amyloid in its stroma.
Biochemical patterns
| Condition | Ca²⁺ | Phosphate | PTH | ALP |
|---|---|---|---|---|
| Primary hyperparathyroidism (adenoma) | ↑ | ↓ | ↑ or inappropriately normal | Normal or ↑ |
| Secondary hyperparathyroidism: CKD | ↓ | ↑ | ↑ | ↑ |
| Secondary hyperparathyroidism: vitamin D deficiency | ↓ or normal | ↓ | ↑ | ↑ |
| Tertiary hyperparathyroidism | ↑ | ↑ | ↑↑ | ↑ |
| Malignancy (PTHrP or bone metastases) | ↑ | ↓ with PTHrP | Suppressed | Variable |
| Sarcoidosis, vitamin D excess | ↑ | ↑ or normal | Suppressed | Normal |
| Immobilisation | ↑ | Normal | Suppressed | Normal |
| Primary hypoparathyroidism | ↓ | ↑ | ↓ | Normal |
| Pseudohypoparathyroidism (PTH resistance) | ↓ | ↑ | ↑ | Normal; short 4th and 5th metacarpals |
| Osteoporosis | Normal | Normal | Normal | Normal |
| Paget disease | Normal | Normal | Normal | ↑↑ |
Chronic kidney disease
Lost nephrons mean less 1α-hydroxylase, so calcitriol falls, gut calcium absorption falls, and phosphate is retained (which also binds calcium and raises FGF23). Result: hypocalcaemia, hyperphosphataemia and raised PTH (secondary hyperparathyroidism), leading to renal osteodystrophy. Treat with alfacalcidol or calcitriol (they bypass the missing enzyme; watch for hypercalcaemia) and phosphate binders. Long-standing stimulation can make the glands autonomous (tertiary).
Hypercalcaemia
- About 90% is primary hyperparathyroidism (outpatients) or malignancy (inpatients). Others: sarcoidosis, vitamin D excess, thiazides, lithium, milk-alkali syndrome, thyrotoxicosis, immobilisation (a young person bedbound after spinal injury: high bone turnover with suppressed PTH), familial hypocalciuric hypercalcaemia, myeloma with renal failure.
- Malignancy mechanisms: PTHrP (squamous carcinoma of lung, a smoker with a hilar mass, calcium 3.4, low phosphate, undetectable PTH); local osteolysis by bone metastases (breast cancer, myeloma) with normal PTHrP; calcitriol from lymphoma. PTHrP is not detected by the PTH assay.
- Primary hyperparathyroidism bone disease: subperiosteal osteoclastic resorption on the radial borders of the middle phalanges, pepper-pot skull, and osteitis fibrosa cystica with brown tumours (haemosiderin-laden giant-cell lesions, not cancers, regressing after parathyroidectomy).
- Features: bone pain, stones, polyuria (nephrogenic DI), constipation, pancreatitis, peptic ulcer, confusion, short QT; metastatic calcification in normal tissues.
- Treatment: IV 0.9% saline first, then a bisphosphonate; loop diuretic only after rehydration; steroids for granulomatous or calcitriol-driven disease.
Hypocalcaemia
- Causes: post-thyroidectomy or parathyroidectomy (hungry bone), vitamin D deficiency, CKD, hypomagnesaemia, pancreatitis, massive transfusion (citrate), alkalosis.
- Features: perioral tingling, carpopedal spasm, Trousseau sign (cuff inflation causes carpal spasm), Chvostek sign, tetany, seizures, long QT.
- Symptomatic tetany the day after thyroidectomy: IV 10% calcium gluconate immediately.
Bone cells and drugs
- Osteoblasts (mesenchymal): make osteoid and ALP; carry PTH receptors; express RANKL and osteoprotegerin. Osteoclasts (monocyte–macrophage lineage): multinucleated, resorb bone in Howship lacunae. Osteocytes: sense load, secrete FGF23 and sclerostin. Remodelling is done by osteoclasts and osteoblasts working together; Volkmann canals run obliquely to connect Haversian canals with the periosteum and medullary cavity.
- Bisphosphonates (alendronate) bind bone mineral, are taken up by resorbing osteoclasts and inhibit farnesyl pyrophosphate synthase, so osteoclasts lose function and undergo apoptosis.
- Denosumab: antibody against RANKL. Teriparatide: intermittent PTH, anabolic.
- Excess thyroxine (TSH suppressed for years) and glucocorticoids increase turnover with net resorption, causing osteoporosis.
Remember PTH: calcium up, phosphate down. Vitamin D: both up. Calcitonin: C cells, medullary carcinoma.
Exam trap Hypercalcaemia with suppressed PTH means a non-parathyroid cause: malignancy, granuloma, vitamin D or immobilisation.
Exam trap 25-hydroxyvitamin D is the measured storage form; calcitriol (1,25) is the active form made in the kidney.
How FCPS asks about this
- Vitamin D metabolite measured in the laboratory: 25-hydroxyvitamin D; active form made by renal 1α-hydroxylase.
- Kidney response to high calcium: more 24,25-dihydroxycholecalciferol.
- CKD with low Ca²⁺, high phosphate, high PTH: lost 1α-hydroxylation; give alfacalcidol or calcitriol.
- Smoker with hilar mass, high Ca²⁺, low phosphate, undetectable PTH: PTHrP from squamous carcinoma.
- Sarcoidosis hypercalcaemia: calcitriol from granulomas; treat with prednisolone.
- Tetany after thyroidectomy: IV 10% calcium gluconate.
- Teriparatide versus hyperparathyroidism: intermittent PTH is anabolic; alendronate inhibits farnesyl pyrophosphate synthase.
Test yourself on this topic
5 of the 69 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 55-year-old woman with long-standing untreated primary hyperparathyroidism has bone pain. Hand X-rays show erosions along the radial borders of the middle phalanges, and the skull has a pepper-pot appearance. What is the underlying bone process?
Answer: Subperiosteal osteoclastic resorption
PTH acts on osteoblasts, which express RANKL and stimulate osteoclasts. Continuously high PTH increases osteoclastic resorption, seen first beneath the periosteum along the radial side of the middle phalanges, at the distal clavicles and as a salt-and-pepper skull. In severe disease, osteitis fibrosa cystica develops, with fibrous replacement of marrow and brown tumours made of osteoclast-like giant cells and haemosiderin. It is rare now because hyperparathyroidism is usually picked up early on routine calcium tests.
Bone in hyperparathyroidism
- High PTH: osteoclasts activated
- Subperiosteal resorption of phalanges
- Pepper-pot skull, clavicle erosion
- Severe: brown tumours (osteitis fibrosa)
Remember Look at the radial side of the middle phalanges.
Exam trap Brown tumours are not cancers; they regress after parathyroidectomy.
Why the other options are wrong
- Defective mineralisation of osteoid That is osteomalacia, with Looser zones.
- Disorganised woven bone remodelling That is Paget disease of bone.
- Avascular necrosis of bone Not the pattern of hyperparathyroidism.
- Metastatic bone destruction No primary tumour is suggested.
A 55-year-old woman has kidney stones, constipation, low mood and calcium 2.9 mmol/L (11.6 mg/dL) with a raised PTH. What is the most likely cause?
Answer: Parathyroid adenoma
Primary hyperparathyroidism, usually from a single parathyroid adenoma, causes high calcium with an inappropriately normal or raised PTH. Features include stones, bone pain and osteoporosis, abdominal pain, constipation, pancreatitis and low mood ('stones, bones, groans and moans'). In malignancy, PTH is suppressed. Symptomatic patients are offered parathyroidectomy after localisation scans.
Primary hyperparathyroidism
- High calcium with high PTH
- Usually an adenoma
- Stones, bones, groans, moans
- Treat: parathyroidectomy
Remember High calcium plus high PTH: parathyroid.
Exam trap Check urine calcium to exclude familial hypocalciuric hypercalcaemia.
Why the other options are wrong
- Bone metastases PTH would be suppressed.
- Vitamin D deficiency Calcium would be low or normal.
- Multiple myeloma PTH suppressed.
- Sarcoidosis PTH suppressed.
A 68-year-old woman has new vertebral fractures despite five years of alendronate. She starts daily subcutaneous teriparatide, a PTH analogue. Why does this build bone, when hyperparathyroidism causes bone loss?
Answer: Intermittent PTH is anabolic
Continuously high PTH keeps RANKL raised and favours net resorption. A short daily peak of PTH instead stimulates osteoblast differentiation and reduces osteoblast apoptosis, partly by lowering sclerostin and boosting Wnt signalling, so formation exceeds resorption for a period. Teriparatide is therefore an anabolic drug that increases bone mass and reduces vertebral fractures. Its use is limited to about two years, and it is avoided where there is a raised risk of osteosarcoma, such as Paget disease or prior skeletal radiation.
Teriparatide
- Continuous PTH: bone loss
- Intermittent PTH: bone formation
- Stimulates osteoblasts
- Limit to ~2 years
Remember Daily pulses build bone; constant PTH destroys it.
Exam trap Teriparatide is an agonist; its effect depends on the timing, not on blocking PTH.
Why the other options are wrong
- Teriparatide blocks PTH receptors It is an agonist, not a blocker.
- It is converted to calcitonin PTH is not converted to calcitonin.
- It acts only on the kidney It acts on bone as well as kidney.
- It inhibits RANKL like denosumab That is denosumab's action, not teriparatide's.
A 60-year-old woman on dialysis absorbs little of her dietary calcium. When she is given calcitriol, her intestinal calcium absorption rises within days. Which of the following is the main mechanism?
Answer: More calbindin and calcium channels
Active calcium absorption takes place mainly in the duodenum and is transcellular. Calcium enters through apical TRPV6 channels, is carried across the cell bound to calbindin, and is pumped out at the basolateral membrane by a calcium ATPase and sodium–calcium exchanger. Calcitriol acts on nuclear vitamin D receptors to increase all three. Passive absorption between cells along the small bowel depends on luminal calcium. In kidney failure, lack of calcitriol reduces absorption and contributes to hypocalcaemia.
Active calcium absorption
- Mainly in the duodenum
- Entry via TRPV6
- Carried by calbindin
- All induced by calcitriol
Remember Calcitriol builds the calcium transport machine in the duodenum.
Exam trap Calcitriol raises phosphate absorption too, which can worsen hyperphosphataemia in kidney failure.
Why the other options are wrong
- Increased gastric acid secretion Not how calcitriol acts.
- Reduced intestinal phosphate absorption Calcitriol increases phosphate absorption too.
- Inhibition of PTH in the gut wall PTH does not act on the gut wall.
- Faster intestinal transit Faster transit would reduce absorption.
After total thyroidectomy with the parathyroids preserved, calcium stays normal without calcitonin replacement. Which of the following best explains this?
Answer: Calcitonin has little role in adult calcium balance
Calcitonin, from the parafollicular C cells of the thyroid, inhibits osteoclasts and can lower calcium, but in adults it has only a minor physiological role. After total thyroidectomy, which removes the C cells, calcium remains normal as long as the parathyroids and vitamin D are intact. Likewise, patients with very high calcitonin from medullary carcinoma do not become hypocalcaemic. PTH and calcitriol are the main regulators of plasma calcium.
Calcitonin
- From C cells of the thyroid
- Inhibits osteoclasts
- Minor role in adults
- Main regulators: PTH and calcitriol
Remember No C cells, no calcium problem.
Exam trap Hypocalcaemia after thyroidectomy is from parathyroid injury, not loss of calcitonin.
Why the other options are wrong
- The parathyroid glands also secrete calcitonin Parathyroid glands make PTH, not calcitonin.
- Levothyroxine replaces the action of calcitonin Thyroxine has no calcitonin-like action.
- The thymus takes over calcitonin production The thymus does not make calcitonin.
- Vitamin D lowers calcium in place of calcitonin Calcitriol raises calcium.
Where this sits in the CPSP syllabus
- Paper 1: Endocrinology, Calcium and bone: PTH, vitamin D, calcitonin
- Surgery & Allied, Paper 2: Endocrinology, Calcium and bone: PTH, vitamin D, calcitonin
- Medicine & Allied, Paper 2: Endocrinology, Calcium and bone: PTH, vitamin D, calcitonin
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