Calcium homeostasis

Both give hypercalcaemia with a PTH that is raised or inappropriately normal, so the PTH does not separate them. The urine does: measure the urinary calcium:creatinine clearance ratio. Below 0.01 suggests familial hypocalciuric hypercalcaemia, an inactivating calcium-sensing receptor mutation in which the kidney reabsorbs calcium avidly; above 0.02 fits primary hyperparathyroidism. Getting this wrong leads to a futile parathyroidectomy, because FHH is benign and needs no treatment.

PTH internalises the NaPi-IIa and NaPi-IIc cotransporters in the proximal tubule, so phosphate is lost in the urine. More PTH means more phosphaturia and a low serum phosphate; no PTH means the transporters stay in the membrane, phosphate is retained and serum phosphate rises. That is why the classic pattern of primary hyperparathyroidism is a high calcium with a low phosphate, and of hypoparathyroidism a low calcium with a high phosphate.

25-hydroxyvitamin D. Its production in the liver is substrate-driven and barely regulated, and it has a half-life of two to three weeks, so it reflects supply over months. Calcitriol has a half-life of only four to six hours and is held up by rising PTH even in deficiency, so it can be normal in a frankly deficient patient and is misleading as a status marker. Measure calcitriol only when asking a specific question, such as suspected granulomatous or lymphoma-related hypercalcaemia.

Because only the ionised fraction matters. Alkalosis, most often from hyperventilation, increases calcium binding to albumin and lowers ionised calcium while leaving total calcium unchanged; citrate given in massive transfusion or apheresis does the same by chelation. The patient gets perioral and digital paraesthesia, carpopedal spasm and a positive Trousseau sign despite a reassuring total calcium, which is why an ionised calcium is the definitive measurement.

No. Osteoclasts have no PTH receptor. PTH1R sits on osteoblasts and osteocytes, which respond by increasing RANKL and decreasing osteoprotegerin, the decoy receptor. RANKL then engages RANK on osteoclast precursors and drives their differentiation and resorptive activity. Calcitonin, by contrast, does act directly on the osteoclast through its own receptor, which is why it stops resorption within minutes.

Primary: calcium high, phosphate low, PTH high or inappropriately normal. Secondary: PTH high with a calcium that is low or low-normal, the phosphate being low in vitamin D deficiency but high in chronic kidney disease. Tertiary: calcium high with a high PTH after years of secondary disease, classically declaring itself after a renal transplant. Hypercalcaemia of malignancy: calcium high with PTH suppressed.

Both conditions block the 1-alpha-hydroxylation step. In chronic kidney disease the proximal tubular CYP27B1 is lost and FGF23 suppresses what remains; in hypoparathyroidism the PTH that normally drives the enzyme is missing. Giving cholecalciferol simply raises 25(OH)D, which cannot be activated, so an already-active analogue such as calcitriol, alfacalcidol or paricalcitol is given instead.

A rise in FGF23, before phosphate, calcitriol or PTH move measurably. Osteocytes respond to early phosphate retention by secreting FGF23, which restores phosphate excretion in the surviving nephrons but also suppresses CYP27B1 and induces CYP24A1, lowering calcitriol. The falling calcitriol and calcium then drive PTH up, and only late in the disease does frank hyperphosphataemia appear.