Bone physiology
Bone physiology: calcium, PTH, vitamin D, remodelling and bone imaging
Calcium, phosphate, PTH, vitamin D and bone remodelling for FCPS Part 1, with biochemistry patterns and imaging. It explains tetany, CKD bone disease, stress reactions, DEXA pitfalls and fluorosis from first principles.
One of the most tested topics in past papers
Calcium in plasma
- 99% of body calcium is in bone as hydroxyapatite. In plasma about 45% is ionised (the active, regulated form), 40% bound to albumin and 15% complexed. Normal total calcium is about 2.2–2.6 mmol/L (8.8–10.4 mg/dL).
- Corrected calcium = total calcium + 0.02 × (40 − albumin in g/L) mmol/L. Low albumin (nephrotic syndrome, cirrhosis, critical illness) lowers the albumin-bound fraction, so total calcium falls while ionised calcium is normal: no tingling, negative Chvostek and Trousseau signs, nothing to treat.
- Alkalosis increases albumin binding and lowers ionised calcium (tetany in hyperventilation). Citrate in massive transfusion binds calcium.
- Low calcium increases nerve membrane permeability to Na⁺ and lowers the threshold: perioral tingling, Chvostek and Trousseau signs, tetany, laryngospasm. High calcium raises the threshold: weakness, hyporeflexia, constipation, short QT.
- Hyperkalaemia with ECG changes (peaked T, broad QRS): the first drug is IV calcium gluconate, which restores the gap between resting potential and threshold and stabilises the myocardium within minutes; it does not lower potassium (insulin–glucose and salbutamol do).
- Hypercalcaemia blocks ADH action on the collecting duct (polyuria, thirst).
- Inside muscle, calcium is stored in the sarcoplasmic reticulum bound to calsequestrin, released through ryanodine receptors and pumped back by SERCA.
The three hormones
| Hormone | Source and trigger | Actions |
|---|---|---|
| PTH | Parathyroid chief cells; low ionised Ca²⁺ sensed by the calcium-sensing receptor | Kidney: more distal Ca²⁺ reabsorption, less proximal phosphate reabsorption, more 1α-hydroxylase. Bone: resorption via osteoblast RANKL (osteoclasts lack PTH receptors) |
| Calcitriol (1,25-dihydroxyvitamin D) | Kidney 1α-hydroxylation, stimulated by PTH and low phosphate | Induces calbindin and calcium channels: the main hormone that increases gut calcium absorption (duodenum); also phosphate absorption; raises both serum calcium and phosphate |
| Calcitonin | Thyroid parafollicular C cells; high calcium | Inhibits osteoclasts; minor role in adults |
- PTH acts through a Gs-coupled receptor and cAMP; it erodes cortical bone first. Continuous PTH causes net resorption, but intermittent PTH (teriparatide) builds bone.
- Magnesium: low Mg²⁺ impairs PTH release and action; correct it before calcium will stay up.
Vitamin D pathway
- Skin: UVB converts 7-dehydrocholesterol to cholecalciferol. Melanin absorbs UVB; covered, indoor mothers and their breastfed babies are at risk.
- Liver 25-hydroxylation, then kidney 1α-hydroxylation. 25-hydroxyvitamin D is the metabolite measured to assess status (long half-life, reflects stores); calcitriol is the active hormone.
- Vitamin D is fat soluble: in obesity it is sequestered in adipose tissue, so the same dose raises the blood level much less; larger doses are needed.
- When calcium is high, the kidney makes inactive 24,25-dihydroxyvitamin D instead.
- Inherited rickets: 1α-hydroxylase deficiency (low calcitriol); vitamin D receptor defect (very high calcitriol, alopecia).
- FGF23 from osteocytes causes phosphaturia and lowers calcitriol (tumour-induced osteomalacia).
Reading the biochemistry
| Condition | Calcium | Phosphate | PTH | Clue |
|---|---|---|---|---|
| Primary hyperparathyroidism (adenoma) | High | Low | High or inappropriately normal | Stones, bones, constipation |
| Familial hypocalciuric hypercalcaemia | Mildly high | Normal | Normal | CaSR mutation; low urinary calcium |
| Malignancy (squamous lung cancer) | High | Low | Suppressed | PTHrP |
| Myeloma | High | Normal | Suppressed | Cytokines activate osteoclasts |
| Vitamin D toxicity | High | High | Suppressed | Supplement history |
| Vitamin D deficiency | Low or normal | Low | High (secondary) | Low 25(OH)D |
| Chronic kidney disease | Low | High | High | Low calcitriol and phosphate retention |
| Hypoparathyroidism (post-thyroidectomy) | Low | High | Low | Tetany on day 1–2 |
| Pseudohypoparathyroidism | Low | High | High | Gs defect; short 4th–5th metacarpals |
- CKD (secondary hyperparathyroidism): failing kidneys make less calcitriol, so gut calcium absorption falls; they also retain phosphate, which binds calcium and stimulates FGF23. The result is hypocalcaemia with raised PTH, and over time renal osteodystrophy. Prolonged stimulation can make the glands autonomous (tertiary hyperparathyroidism, calcium high).
- Hungry bone syndrome: after parathyroidectomy, demineralised bone takes up calcium, phosphate and magnesium avidly.
Bone cells, remodelling and strength
- Osteoblasts lay down osteoid, secrete alkaline phosphatase and express RANKL; osteoprotegerin is the decoy receptor.
- Osteoclasts are multinucleated cells of monocyte lineage. Osteocytes sense load and secrete sclerostin, which brakes formation.
- Remodelling is done by basic multicellular units of osteoclasts and osteoblasts in the order activation, resorption, reversal, formation. Resorption takes about 3 weeks, formation about 3 months.
- Stress reaction: a sudden rise in load (recruits in week 3 of marching) triggers many new remodelling units. Because resorption comes first and formation lags, the bone is transiently more porous and weakest a few weeks in: marrow oedema on MRI without a fracture line.
- Disuse (a limb in plaster, bed rest, microgravity) removes the loading signal: osteocytes release more sclerostin and RANKL, so bone is resorbed and muscle atrophies.
- Bone strength depends on mass and on quality: collagen arrangement, trabecular microarchitecture, mineralisation and microdamage repair.
- Sex steroids: androgens and oestrogen drive the pubertal growth spurt, but oestrogen (made from testosterone by aromatase in males) closes the growth plates, so growth stops. Oestrogen loss after menopause raises osteoclast activity.
- Stopping denosumab gives a rebound surge in osteoclasts. Long bisphosphonate use suppresses microdamage repair (atypical subtrochanteric fracture).
- Osteosarcoma is the commonest primary malignant bone tumour in the second decade (metaphysis around the knee).
Pregnancy and lactation
- Maternal calcitriol doubles, so gut absorption doubles; the placenta pumps calcium actively, driven by fetal PTHrP.
- Lactation: breast PTHrP plus low oestradiol mobilise maternal bone; milk calcium stays normal even on a poor diet.
Imaging correlation
| Finding | Mechanism |
|---|---|
| Osteoporosis: thin, sparse trabeculae, wedge fractures | Less bone, normally mineralised; biochemistry normal |
| Osteomalacia: Looser zones | Unmineralised osteoid |
| Rickets: widened physis, cupped, frayed metaphyses | Failed mineralisation of hypertrophic cartilage |
| Scurvy: ground-glass bone, dense metaphyseal line | Poor collagen formation |
| Fluorosis: diffusely dense vertebrae, ligament and interosseous membrane calcification, mottled teeth | Fluorapatite replaces hydroxyapatite; dense but brittle bone (high-fluoride well water, e.g. Tharparkar) |
| Paget disease: advancing V-shaped lytic front | Large osteoclasts with many nuclei |
| Myeloma: punched-out lesions, often normal bone scan | Lysis without osteoblastic response |
| Hot spots on Tc-99m MDP bone scan | Tracer binds new hydroxyapatite at osteoblastic sites |
| Medial arterial calcification in CKD | Osteoblast-like change in smooth muscle |
- DEXA measures all mineral in the beam path. In an elderly man, osteophytes and a calcified aorta add mineral to the lumbar spine reading and give a falsely normal T-score; trust the hip, or use quantitative CT. T-score of −2.5 or below is osteoporosis.
- Calcified old tuberculous nodes are dystrophic calcification (normal serum calcium).
Remember PTH raises calcium and lowers phosphate; calcitriol raises both; in CKD calcium falls and phosphate and PTH rise.
Exam trap A raised calcium with suppressed PTH is not hyperparathyroidism: think PTHrP, myeloma or vitamin D excess.
Exam trap Low total calcium with low albumin and no symptoms is usually normal ionised calcium: correct it before treating.
How FCPS asks about this
- CKD and reduced calcitriol: hypocalcaemia, hyperphosphataemia and raised PTH.
- Low total calcium in nephrotic syndrome, no tetany: reduced albumin-bound fraction.
- Metabolite measured for vitamin D status: 25-hydroxyvitamin D; calcitriol increases gut calcium absorption.
- Shin pain in week 3 of training: resorption precedes slower formation.
- Normal spine DEXA with osteophytes and aortic calcification: extra mineral in the beam.
- Dense vertebrae and mottled teeth from well water: fluorapatite in bone.
- First drug for hyperkalaemia with ECG changes: IV calcium gluconate.
Test yourself on this topic
5 of the 91 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
Bone mass increases with mechanical loading partly because osteocytes then secrete less of a protein that inhibits Wnt signalling in osteoblasts. Which protein is this?
Answer: Sclerostin
Sclerostin is secreted by osteocytes buried in mineralised bone and inhibits Wnt signalling in osteoblasts, holding back bone formation. Mechanical loading reduces sclerostin, releasing the brake, which is how bone adapts to use; immobilisation raises it. RANKL from osteoblasts and osteocytes drives osteoclasts, and osteoprotegerin is its decoy receptor. The anti-sclerostin antibody romosozumab exploits this pathway to build bone.
Sclerostin
- Secreted by osteocytes
- Inhibits Wnt signalling
- Loading lowers sclerostin
- Disuse raises it
Remember Osteocytes sense load and release the brake on bone formation.
Exam trap Confusing sclerostin (osteocyte Wnt inhibitor) with RANKL (osteoclast driver).
Why the other options are wrong
- RANK ligand Stimulates osteoclast formation, not a Wnt inhibitor.
- Osteoprotegerin Decoy receptor for RANKL; protects bone.
- Cathepsin K Osteoclast enzyme that digests collagen.
- Parathyroid hormone receptor Receptor for PTH and PTHrP, not a secreted inhibitor.
A 55-year-old woman with primary hyperparathyroidism has DEXA T-scores of −0.8 at the lumbar spine, −1.5 at the hip and −2.9 at the distal one-third of the radius. Why is the radius most affected?
Answer: PTH mainly erodes cortical bone
Continuous high PTH preferentially thins cortical bone by endosteal resorption, while trabecular bone is relatively preserved. The distal one-third of the radius is almost purely cortical, so it shows the greatest loss. The lumbar spine is mostly trabecular and often looks near normal. Measuring the forearm is therefore part of DEXA in hyperparathyroidism.
PTH and bone sites
- PTH thins cortical bone
- Trabecular bone relatively spared
- Distal ⅓ radius mostly cortical
- Measure the forearm in PHPT
Remember Hyperparathyroidism: check the distal radius.
Exam trap A near-normal spine DEXA does not exclude hyperparathyroid bone loss.
Why the other options are wrong
- PTH mainly erodes trabecular bone That pattern fits oestrogen or steroid loss.
- The radius bears most body weight The radius is not weight-bearing.
- Spine readings are falsely low Spine readings would be falsely high, if anything.
- Forearm bone has no PTH receptors Osteoblasts in all bones carry PTH receptors.
A 25-year-old woman from Lahore working in Manchester has a low 25-hydroxyvitamin D despite walking outdoors daily. Why does darker skin produce less vitamin D for the same sun exposure?
Answer: Melanin absorbs UVB photons
Ultraviolet B (about 290–315 nm) converts 7-dehydrocholesterol in the skin to previtamin D3. Melanin absorbs UVB, so more pigmented skin needs several times the exposure to make the same amount of vitamin D. Weak winter UVB at high latitude makes this worse. UVA does not drive vitamin D synthesis.
Skin vitamin D
- UVB on 7-dehydrocholesterol
- Melanin absorbs UVB
- Dark skin needs longer exposure
- Weak UVB at high latitude
Remember More melanin, less vitamin D per hour of sun.
Exam trap UVA does not make vitamin D; only UVB does.
Why the other options are wrong
- Less 7-dehydrocholesterol in skin Precursor content is similar.
- Faster hepatic 25-hydroxylation Would raise, not lower, 25-OH vitamin D.
- Thicker stratum corneum blocks UVA UVA is not the wavelength used.
- More vitamin D-binding protein Not the cause of low synthesis.
Before an iliac crest bone biopsy, a dialysis patient takes two short courses of oral tetracycline separated by 10 days. Under fluorescence microscopy, two bright lines are seen in the bone and the gap between them is measured. Why does tetracycline label bone in this way?
Answer: It binds calcium at the mineralisation front
Tetracyclines chelate calcium and are incorporated into hydroxyapatite where new mineral is being laid down, at the junction of osteoid and mineralised bone. Each course leaves a fluorescent line, and the distance between the two lines divided by the time interval gives the mineral apposition rate. In osteomalacia the labels are smudged or absent; in adynamic bone they are scanty. The same calcium binding stains developing teeth.
Tetracycline labelling
- Tetracycline chelates calcium
- Laid down at the mineralisation front
- Two labels give the apposition rate
- Smudged labels: osteomalacia
Remember Tetracycline marks where mineral is being laid down.
Exam trap The same calcium binding explains tetracycline staining of children's teeth.
Why the other options are wrong
- It is taken up by active osteoclasts Labels sites of formation, not resorption.
- It stains unmineralised osteoid red Fluorescence, not a red stain, and osteoid is not labelled.
- It binds type I collagen fibres in osteoid Binding is to mineral, not collagen.
- It collects in empty osteocyte lacunae Not the basis of the labels.
A 19-year-old army recruit develops localised tibial pain and tenderness in week 3 of intensive marching training (a stress reaction). Why is bone weakest a few weeks into a sudden increase in load?
Answer: Resorption precedes slower formation
New loading triggers remodelling to repair microdamage and adapt bone. In each remodelling unit, osteoclasts resorb first, over about 2–4 weeks, and osteoblasts then refill the cavity over about 3 months. During the early weeks the bone is temporarily more porous and weaker, so stress reaction and stress fracture are common at this stage. Load itself is anabolic in the long term.
Remodelling cycle
- Activation, resorption, reversal, formation
- Resorption weeks
- Formation months
- Early loading: porous, weaker bone
Remember Resorption is quick; formation is slow.
Exam trap Thinking new training immediately strengthens bone.
Why the other options are wrong
- Exercise inhibits osteoblast function Loading stimulates osteoblasts over time.
- Periosteal bone is lost first Periosteal bone is not preferentially lost.
- Gut calcium absorption falls Not the mechanism of stress injury.
- Cortical bone converts to woven bone Woven bone appears only in healing, not in normal loading.
Where this sits in the CPSP syllabus
- Diagnostic Radiology, Paper 2: Endocrine and reproductive physiology, Bone physiology: calcium, PTH, vitamin D and remodelling
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