Bone: osteoblast-osteoclast coupling
Target organ · RANKL up, OPG down Denosumab
Bone holds about 99% of body calcium. PTH does not act on the osteoclast: PTH1R sits on osteoblasts and osteocytes, which answer by raising RANKL and lowering osteoprotegerin, so RANK-bearing osteoclast precursors mature and resorb mineral. Calcitonin acts on the osteoclast directly and switches resorption off.
Traced from the start
Detail
- Signalling
- PTH acts on osteoblast and osteocyte PTH1R, raising RANKL and lowering osteoprotegerin, the decoy receptor; RANKL then engages RANK on osteoclast precursors to drive differentiation and resorption
- Timing
- Rapid calcium efflux from bone fluid within minutes by osteocytic osteolysis, then osteoclastic resorption over hours to days
- Calcitonin
- Binds the calcitonin receptor on the osteoclast itself and inhibits resorption within minutes
- Chemistry
- Mineral is hydroxyapatite, Ca10(PO4)6(OH)2, so resorption releases phosphate along with calcium; alkaline phosphatase, an osteoblast product, rises whenever turnover is high
When it goes wrong
Long-standing severe hyperparathyroidism
Osteitis fibrosa cystica: subperiosteal resorption on the radial side of the middle phalanges, a pepper-pot skull, brown tumours and a raised alkaline phosphatase
Denosumab, an anti-RANKL antibody, given to a vitamin D-deficient patient
Severe symptomatic hypocalcaemia; correct vitamin D and calcium before starting, and never stop it without follow-on antiresorptive therapy because of rebound vertebral fractures
Immobilisation, Paget disease of bone or osteolytic metastases
Uncoupled resorption raises serum calcium with an appropriately suppressed PTH
Practise this structure
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