Calcium & Bone Endocrinology

Hormones of calcium and phosphate balance

PTH raises calcium, drops phosphate. Parathyroid chief cells sense low calcium through the calcium-sensing receptor (CaSR) and release PTH, which acts through Gs/cAMP. PTH increases bone resorption indirectly: osteoblasts express RANKL, which activates osteoclasts. In the kidney it raises distal-tubule calcium reabsorption, dumps phosphate in the urine by blocking proximal-tubule reabsorption, and activates 1α-hydroxylase to make calcitriol. The net effect is calcium up, phosphate down and urinary cAMP up. Continuous PTH excess destroys bone, whereas intermittent dosing (teriparatide) builds it.

Vitamin D needs two hydroxylations. UVB converts 7-dehydrocholesterol in the skin to cholecalciferol (D3); the liver 25-hydroxylates it to 25-OH-D, the storage form measured to assess vitamin D status; renal 1α-hydroxylase then makes 1,25-(OH)2-D (calcitriol), the active hormone. Calcitriol raises gut absorption of both calcium and phosphate, supporting bone mineralization. Deficiency causes rickets in children and osteomalacia in adults.

Calcitonin tones calcium down. Parafollicular C cells of the thyroid release calcitonin when calcium is high; it inhibits osteoclasts, opposing PTH. Its physiologic role in humans is minor, but a rising level flags medullary thyroid carcinoma.

FGF23 is the phosphate brake. Osteocytes secrete FGF23 when phosphate is high. It promotes renal phosphate wasting and inhibits 1α-hydroxylase, lowering calcitriol. Excess FGF23 causes hypophosphatemic rickets and osteomalacia, as in X-linked hypophosphatemia (PHEX mutation) and tumor-induced osteomalacia.

Ionized calcium and neuromuscular signs

Only ionized calcium counts. About 40% of serum calcium is bound to albumin; the free, ionized fraction is physiologically active. When albumin is low, total calcium must be corrected upward before calling hypocalcemia.

pH shifts binding. Alkalosis increases albumin binding and drops ionized calcium without changing the total, producing perioral tingling, cramps, tetany and Chvostek and Trousseau signs. Hyperventilation from anxiety is the classic example: respiratory alkalosis causes tingling and carpopedal spasm.

Signs of hypocalcemia. Chvostek sign is facial twitching when the facial nerve is tapped; Trousseau sign is carpal spasm when a blood-pressure cuff is inflated. The ECG shows a prolonged QT, whereas hypercalcemia shortens it.

Hypomagnesemia impairs both PTH secretion and PTH action, so hypocalcemia will not correct until magnesium is replaced.

Hyperparathyroidism and hypercalcemia

Primary hyperparathyroidism. A single parathyroid adenoma (~85%) secretes PTH autonomously: high calcium, low phosphate, high PTH, with hypercalciuria and raised alkaline phosphatase. It is the most common cause of hypercalcemia in outpatients. Symptoms are "stones, bones, groans and psychiatric overtones": kidney stones, bone pain, constipation and abdominal pain, and depression or confusion. Severe bone disease is osteitis fibrosa cystica, with cystic spaces filled with fibrous tissue and hemosiderin-laden brown tumors. Hyperplasia of all glands suggests MEN 1 or MEN 2A. Treatment is parathyroidectomy.

Secondary hyperparathyroidism. In chronic kidney disease, phosphate cannot be excreted and calcitriol production falls, lowering calcium; the glands compensate with high PTH. The pattern is low or normal calcium, high phosphate and high PTH, and the bone disease is renal osteodystrophy. Vitamin D deficiency also causes secondary hyperparathyroidism, but with low phosphate. Phosphate binders, calcitriol and the calcimimetic cinacalcet control it.

Tertiary hyperparathyroidism. After years of secondary stimulation, the hyperplastic glands secrete PTH autonomously. Calcium now swings high with very elevated PTH, classically after renal transplant.

Secondary = high PTH with low or normal calcium; tertiary = the same glands now push calcium high.

Humoral hypercalcemia of malignancy. Squamous cell carcinomas of the lung and head and neck, renal cell, bladder and breast cancers secrete PTH-related peptide (PTHrP). It mimics PTH on the labs (high calcium, low phosphate) but feedback suppresses native PTH. Malignancy is the most common cause of hypercalcemia in hospitalized patients.

Other causes. Vitamin D toxicity and granulomatous disease such as sarcoidosis (macrophages express 1α-hydroxylase) raise both calcium and phosphate with low PTH. Familial hypocalciuric hypercalcemia, an inactivating CaSR mutation, causes benign mild hypercalcemia with normal or mildly raised PTH and low urinary calcium, and needs no surgery.

Treating hypercalcemia. Over 90% of hypercalcemia is primary hyperparathyroidism (outpatients) or malignancy (inpatients). Acute treatment starts with IV saline, since hypercalcemia causes polyuria and volume depletion; calcitonin then lowers calcium within hours but loses effect over a couple of days, while bisphosphonates take several days to act but give durable control. Glucocorticoids help calcitriol-driven (granulomatous) hypercalcemia.

Hypoparathyroidism and PTH resistance

Hypoparathyroidism. Loss of PTH, most often from accidental removal of the glands during thyroidectomy or from DiGeorge syndrome (22q11.2 deletion with absent parathyroids), gives low calcium, high phosphate and low PTH. Neuromuscular irritability follows: perioral numbness, Chvostek and Trousseau signs, tetany and a prolonged QT. Treatment is calcium plus calcitriol.

Pseudohypoparathyroidism. In Albright hereditary osteodystrophy (pseudohypoparathyroidism type 1A), a maternally inherited Gs-α (GNAS) defect causes end-organ resistance to PTH. The glands pump out high PTH, but calcium stays low and phosphate high. The phenotype is short stature, a round face, obesity and shortened 4th and 5th metacarpals. When the same defect is inherited on the paternal allele, patients have the look but normal calcium (pseudopseudohypoparathyroidism).

Imprinting: a maternal GNAS defect gives resistance and low calcium; a paternal defect gives the same appearance with normal calcium.

Reading the calcium–phosphate–PTH triad

A logic for the triad. Ask first whether PTH is appropriate: low PTH with high calcium means a PTH-independent source (PTHrP, vitamin D), while high PTH with low calcium means the glands are compensating (CKD, vitamin D deficiency) or the target organ is resistant (pseudohypoparathyroidism). Phosphate then points to the kidney: high phosphate with high PTH implies renal failure or PTH resistance, because a functioning kidney would waste phosphate.