Calcium Homeostasis
On this page
Direct answer
Plasma calcium is held at 9-11 mg/dL (ionised fraction about half, 4.4-5.4 mg/dL) by three hormones acting on bone, gut and kidney: parathyroid hormone raises calcium by stimulating osteoclastic resorption through RANKL, enhancing distal tubular calcium reabsorption and phosphaturia, and driving renal 1-alpha-hydroxylase to make calcitriol; calcitriol raises intestinal calcium absorption from a basal 15-20% to 30-40% by inducing calbindin; and calcitonin, from thyroid C cells, weakly opposes resorption. The calcium-sensing receptor on parathyroid chief cells senses ionised calcium minute-to-minute, making PTH the fast defence against hypocalcaemia and bone the instant buffer.
What you must remember
- Distribution and forms: 99% skeletal; plasma total 9-11 mg/dL with about 50% ionised, 40% protein-bound (mainly albumin), 10% complexed — correct total calcium by 0.8 mg/dL for every 1 g/dL albumin below 4 g/dL.
- Ionised is the active fraction: alkalosis lowers it (more binding) and precipitates tetany; acidosis raises it — the reason a hypocalcaemic patient convulses when over-ventilated.
- PTH essentials: 84-amino-acid hormone from chief cells, released when the calcium-sensing receptor detects falling ionised calcium; acts in minutes on bone and kidney, hours-days via calcitriol; intact PTH 1-84 is the assay.
- Vitamin D cascade: cholecalciferol (skin, UVB on 7-dehydrocholesterol) to 25-OH-D in liver (best storage marker) to 1,25(OH)2D3 by renal 1-alpha-hydroxylase — stimulated by PTH and hypophosphataemia, inhibited by FGF-23 and by calcitriol itself.
- Bone cell control: PTH and calcitriol induce RANKL on osteoblasts, activating osteoclast precursors; osteoprotegerin is the decoy receptor — denosumab, a RANKL antibody, and oestrogen's antiresorptive effect act right here.
- Renal handling: about 98-99% of filtered calcium is reabsorbed — 60-70% proximal (paracellular, sodium-linked), 25% thick ascending limb (paracellular, driven by the lumen-positive potential), 5-10% distal (transcellular TRPV5, PTH-stimulated); thiazides act at the distal site and retain calcium.
- Clinical signs: Chvostek (facial nerve tap) and Trousseau (cuff inflation carpopedal spasm) for hypocalcaemia; hypercalcaemia gives stones, bones, abdominal groans and psychiatric overtones.
- CaSR disorders: loss-of-function causes familial hypocalciuric hypercalcaemia (mimics primary hyperparathyroidism but with low urinary calcium); gain-of-function causes autosomal dominant hypocalcaemia.
How to work through a calcium abnormality
A 55-year-old post-thyroidectomy woman with perioral tingling on postoperative day 1: Trousseau sign positive, total calcium 7.2 mg/dL, phosphate high-normal. The pattern is parathyroid injury or removal — PTH cannot mobilise bone or retain distal calcium, so calcium falls while phosphate climbs (no phosphaturia). Intravenous calcium gluconate controls symptoms; most transient hypoparathyroidism recovers within weeks.
Contrast a 60-year-old with fatigue, constipation, calcium 12.8 mg/dL, phosphate low and intact PTH inappropriately normal-to-high: primary hyperparathyroidism, the commonest cause of outpatient hypercalcaemia, with PTH inappropriately normal or high for that calcium level. Here PTH's phosphaturia explains the low phosphate, and the hypercalcaemia comes from osteoclast resorption plus calcitriol-driven gut absorption. Malignancy hypercalcaemia (PTH-related peptide, osteolysis, or calcitriol in lymphoma and granulomatous disease) suppresses PTH instead — the two-way PTH interpretation is the diagnostic fulcrum. Acute severe hypercalcaemia is treated with saline loading to restore the sodium-linked proximal reabsorption of calcium (washed out by dehydration) plus bisphosphonates that poison osteoclasts over 2-4 days; calcitonin gives faster but tachyphylactic cover in between.
Where students slip
Students credit calcitonin with a major role in adult human calcium balance; it is physiologically minor (thyroidectomy does not cause hypercalcaemia), important mainly as a tumour marker and agent in Paget disease. The second slip is calling PTH a direct osteoclast hormone: osteoclasts lack PTH receptors — osteoblast-stromal cells relay the signal through RANKL, a fact that explains both denosumab and the osteoprotegerin story. Finally, candidates forget that vitamin D's first duty in primordial evolution was calcium absorption, not bone mineralisation per se — but the exam-relevant formulation is simpler: PTH is the rapid defence, calcitriol the absorption defence, bone the reservoir, and the CaSR the sensor; say those four in order.
Frequently asked questions
Which fraction of plasma calcium is physiologically active?
The ionised half, about 4.4-5.4 mg/dL; protein-bound calcium rises in hyperalbuminaemia and falls in hypoalbuminaemia without symptoms, so corrected calcium or ionised measurement guides decisions.
How does PTH raise plasma calcium?
RANKL-mediated osteoclastic resorption of bone, increased distal tubular calcium reabsorption, and stimulation of renal 1-alpha-hydroxylase generating calcitriol, which increases intestinal absorption.
Why does alkalosis cause tetany in a borderline patient?
Alkalosis increases calcium binding to albumin, lowering the ionised fraction; nerves become hyperexcitable at the same total calcium — the classic example is hyperventilation-induced carpopedal spasm.
What is the role of the calcium-sensing receptor?
A G-protein receptor on parathyroid chief cells (and renal tubules) that suppresses PTH when ionised calcium rises; activating mutations cause hypocalcaemia and inactivating mutations familial hypocalciuric hypercalcaemia.
Why is 25-hydroxyvitamin D measured rather than calcitriol?
25-OH-D has a long half-life and reflects intake and skin synthesis — the storage index — whereas calcitriol is tightly regulated and normal until late, so it masks deficiency.