Calcium homeostasis

Calcium must be tightly controlled because the ionized fraction sets the excitability of nerve and muscle membranes and triggers muscle contraction. Circulating calcium exists in three forms: roughly half is free ionized calcium, the physiologically active form; about 40% is bound to albumin; and a small remainder is complexed with anions such as phosphate and citrate. Only the ionized fraction is regulated, which is why hypoalbuminemia lowers total serum calcium without producing symptoms, and why alkalosis — which increases calcium binding to albumin — can cause tetany even when total calcium is normal.

Parathyroid hormone is the moment-to-moment regulator. Chief cells of the parathyroid glands sense a fall in ionized calcium through a calcium-sensing receptor and release PTH, which raises calcium by three routes: it stimulates osteoclast-mediated bone resorption indirectly through osteoblast signaling, it increases calcium reabsorption in the distal tubule of the kidney, and it activates 1α-hydroxylase in the proximal tubule to produce active vitamin D. PTH also decreases proximal tubular phosphate reabsorption, so it raises calcium while lowering phosphate.

Calcitriol, the active form of vitamin D, is the longer-term regulator. Skin synthesis or dietary intake yields vitamin D, which is hydroxylated in the liver to 25-hydroxyvitamin D and then in the kidney to 1,25-dihydroxyvitamin D. Calcitriol increases intestinal absorption of both calcium and phosphate and assists bone resorption, so unlike PTH it raises both ions. Calcitonin, released by thyroid parafollicular C cells when calcium rises, inhibits osteoclasts and lowers calcium, but its physiologic role in humans is minor. Magnesium is a necessary cofactor for PTH secretion, so severe hypomagnesemia produces a functional hypoparathyroidism.

USMLE Step 1 tests calcium homeostasis in the endocrine physiology material, typically through lab panels: a pattern of high calcium with low phosphate points toward PTH excess, while high calcium with high phosphate suggests a vitamin D–mediated process. The MCAT covers the same regulation within the muscular and skeletal systems, emphasizing bone as the body's calcium reservoir and the role of ionized calcium in muscle contraction.