Calcium and parathyroid hormone

The three hormones

• PTH acts through a Gs, cAMP receptor. Osteoclasts lack PTH receptors; osteoblasts present RANKL, and osteoprotegerin (OPG) is the decoy that blocks it.
• Calcitriol is the hormone that increases calcium absorption from the gut; it raises both serum calcium and phosphate.
• Vitamin D pathway: 7-dehydrocholesterol + UVB in skin gives cholecalciferol; liver 25-hydroxylation; kidney 1-alpha-hydroxylation. 25-hydroxyvitamin D is measured in the laboratory because it is the stable circulating store with a long half-life; calcitriol is the active form.
• Less vitamin D is made in dark skin, with full covering or staying indoors; it is sequestered in fat in obesity. Phytate in wholemeal chapati binds calcium.
• Excitability: low calcium lowers the threshold for sodium channel opening (tetany, Chvostek and Trousseau signs); high calcium raises it (weakness, constipation) and blocks ADH action (polyuria).
• Corrected calcium (mmol/L) = total + 0.02 x (40 minus albumin in g/L). Calcium 2.5 mmol/L equals 10 mg/dL (multiply by 4).
• Inside muscle, calsequestrin binds and stores calcium in the sarcoplasmic reticulum, releasing it through the ryanodine receptor.

Parathyroid glands

• Usually four. Superior glands come from the 4th pharyngeal pouch; inferior glands from the 3rd pouch (with the thymus), so they migrate further and are more often ectopic.
• Both pairs are supplied mainly by the inferior thyroid artery (thyrocervical trunk); the superior glands may also get branches from the superior thyroid artery.

Renal handling of calcium

• Thiazides raise serum calcium and lower urinary calcium (used for calcium stones); they are the classic drug that worsens hypercalcaemia. Lithium and excess vitamin D also raise it.

Reading calcium, phosphate and PTH

• CKD: failing kidneys cannot make calcitriol and retain phosphate, so calcium falls and PTH rises (secondary hyperparathyroidism, renal osteodystrophy).
• Pseudohypoparathyroidism: end-organ resistance (Gs alpha defect); no cAMP response to PTH. Low calcium with high phosphate and high PTH.
• In primary hyperparathyroidism urinary calcium is high because the filtered load is high; cortical bone (distal radius) suffers most.
• PTHrP from squamous lung cancer or small cell carcinoma of the ovary, hypercalcaemic type causes hypercalcaemia with suppressed PTH. Lymphoma makes calcitriol.

Pregnancy

• The placenta pumps calcium actively, so fetal calcium is higher than maternal. Fetal PTHrP, not PTH, mainly drives this transport: without PTHrP placental transport falls even when PTH is present. The two share the PTH1 receptor but have different roles. Most fetal mineral is laid down in the third trimester.
• Calcium supplements in women with low intake reduce pre-eclampsia.
• Magnesium sulphate: Mg2+ competes with calcium at presynaptic calcium channels and reduces acetylcholine release. In toxicity, knee jerks disappear first (about 7 mmol/L), then respiration fails; IV calcium gluconate works by competing with Mg2+ at the nerve terminal.
• During infusion serum calcium falls mainly because high magnesium suppresses PTH secretion (plus increased urinary calcium loss). A mild fall needs no calcium.
• Long-term unfractionated heparin causes osteoporosis.
• Osteomalacia in adult life softens a fully formed pelvis, which collapses under body weight into a triradiate pelvis (indented from both sides and by the promontory, Y-shaped inlet). Childhood rickets produces a flat (platypelloid) inlet instead.

Lactation and the newborn

• Exclusive breastfeeding removes about 5% of spinal bone over six months: PTHrP from the breast plus low oestrogen of lactational amenorrhoea. It recovers after weaning.
• After birth the placental supply stops; neonatal calcium falls to a nadir at 24–48 hours while PTH rises.

• Rickets on X-ray: wide growth plate with cupping and fraying of metaphyses.

Bone remodelling and menopause

• Remodelling cycle: activation, resorption, reversal, formation, then quiescence. Mechanical loading drives formation, so immobility and microgravity (astronauts) cause rapid bone loss with muscle atrophy and hypercalciuria.
• Oestrogen loss raises RANKL, IL-1, IL-6 and TNF, lowers OPG and prolongs osteoclast life. More remodelling units open and each removes more than it replaces.
• Trabecular bone is lost fastest in early menopause, so vertebral crush and distal radius fractures come first; hip fracture follows later.
• Osteoporosis has normal calcium, phosphate and alkaline phosphatase; osteomalacia has low phosphate and high ALP and PTH.
• Low-oestrogen states at any age cause bone loss. GnRH agonists (goserelin for endometriosis) are limited to about 6 months unless low-dose HRT add-back is given, which protects bone while keeping the benefit.

Remember PTH: raise calcium, dump phosphate, make calcitriol. Pregnancy: absorb more, do not resorb more.

Exam trap A low total calcium in pregnancy is usually dilutional; check ionised or corrected calcium.

Exam trap Osteoclasts have no PTH receptors; PTH works through osteoblast RANKL.

How FCPS asks about this

• Vitamin D metabolite measured in the laboratory: 25-hydroxyvitamin D; the active form is 1,25-dihydroxyvitamin D.
• Low calcium, high phosphate, high PTH: chronic kidney disease or pseudohypoparathyroidism (end-organ resistance).
• Most filtered calcium is reabsorbed in: the proximal convoluted tubule; PTH and thiazides act distally.
• Calcitonin is secreted by: parafollicular C cells; raised in medullary thyroid carcinoma.
• Blood supply of the parathyroids: inferior thyroid artery for both pairs.
• Calcium gluconate reverses magnesium toxicity by: competing with Mg2+ at presynaptic calcium channels.
• Drug that raises serum calcium further: a thiazide diuretic.