Coupled homeostatic loop. Plasma Ca2+ low → parathyroid CaSR senses → PTH released → (1) bone: stimulates osteoclast resorption via RANKL on osteoblasts; (2) kidney: increases Ca2+ reabsorption + PO4 excretion + activates CYP27B1 → calcitriol; (3) gut: indirect via calcitriol → upregulates calbindin / TRPV6 for active Ca absorption. Net: plasma Ca rises. Inverse for high Ca → calcitonin from thyroid C cells (lesser role in humans). Pharmacology: bisphosphonates inhibit osteoclasts (alendronate, zoledronate); denosumab is anti-RANKL mAb; teriparatide is recombinant PTH(1-34) — paradoxically anabolic when given pulsatile (vs continuous which is resorptive); romosozumab is anti-sclerostin (Wnt activator → bone formation); cinacalcet is a CaSR PAM for secondary hyperPTH + parathyroid carcinoma.
Organ Systems
endocrine
musculoskeletal
renal
Pathway Steps
low-plasma-calcium → pth-release — via CaSR senses → parathyroid chief cells release PTH. A fall in plasma ionized calcium is sensed by the parathyroid calcium-sensing receptor (CaSR), which triggers PTH secretion within minutes. The CaSR is exquisitely sensitive, making PTH the rapid, first-line defense of calcium homeostasis — and the target of calcimimetics (cinacalcet) that lower PTH.
pth-release → bone-resorption — via RANKL-mediated osteoclast activation. PTH stimulates osteoclastic bone resorption (indirectly, via RANKL on osteoblasts), releasing calcium and phosphate from the skeleton. Continuous high PTH is catabolic to bone (as in hyperparathyroidism), whereas intermittent PTH is anabolic — the paradox exploited by teriparatide for osteoporosis.
pth-release → renal-calcium-reabsorption — via distal tubule TRPV5 + calbindin. In the kidney, PTH increases distal tubular calcium reabsorption (conserving calcium) while inhibiting proximal phosphate reabsorption (promoting phosphaturia). This dual renal action raises serum calcium while preventing the phosphate co-released from bone from accumulating.
pth-release → calcitriol-synthesis — via renal CYP27B1 activation (see vitamin_d_metabolism). PTH also induces renal 1α-hydroxylase (CYP27B1) to make active calcitriol (1,25-D), which raises intestinal calcium absorption — the slower, third arm of PTH action. This ties the PTH-calcium axis to vitamin D status; deficiency causes secondary hyperparathyroidism.
Known Modulators
cholecalciferol (substrate) — axis component (supports gut Ca absorption)