Calcium and Phosphate Homeostasis 05/04/05 Calcium ~10mg/dL in body -kept under tight control GI tract net absorbs 200mg/day Kidney reabsorbs 98% of that 99% of Ca in body is stored in bone Phosphate GI tract only absorbs PO4 Kidney reabsorbs ~90% of that Some PO4 is transported from soft tissue to plasma when plasma levels are low Bone stores the rest Hormone Regulation Parathyroid Hormone (PTH) →↑plasma [Ca++] and ↓plasma [PO4] 1,25-Vitamin D→↑plasma [Ca++] and ↑plasma [PO4] Calcitonin→↓plasma [Ca++] and ↓plasma [PO4] PTH Produced from parathyroid chief cells 84aa, half-life of 20 min Activates via cAMP Stimulated by: -↓plasma [Ca++] -↓Mg++ Inhibited by: -1,25-Vit. D Effect on Kidney: -↑reabsorption of Ca++ -↓reabsorption of PO4 -↑1,25-Vit. D production Effect on Bone -Stimulate osteolysis (by osteoclasts) -Inhibit collagen production (by osteoblasts) Effect on GI: -↑absorption of Ca++ and PO4 (because of Vit. D prod.) Calcitonin-“Calci-bone-in” Produced from thyroid parafollicular cells (calcitonin cells, C-cells) 32aa, half-life of 10 min Activates via cAMP Stimulated by: -↑plasma [Ca++] -Gastrin -β-agonists, DA, estrogens

Effect on Bone: -↓osteolysis and bone resorption -↑bone formation 1,25(OH)2-Vitamin D Synthesized from cholesterol or acquired from diet Half-life of days to weeks Fat-soluble, so binds nuclear receptor -induces translation of Calcium Binding Protein in GI and kidney Two forms of Vit. D: -1,25-dihydroxy Vit. D (active form) -enzyme = 1-hydroxylase Stimulated by: -↓1,25-Vit. D -↓Ca++ -↓ PO4 -↑PTH -Prolactin Inhibited by: -Hyperthyroidism -24,25-dihydroxy Vit. D (inactive form) -enzyme = 24-hydroxylase Stimulated by: -↑1,25-Vit. D -↑Ca++ -↑ PO4 Effect on Kidney: -↑Ca++ and PO4 reabsorption Effect on Bone: -↑bone resorption (with PTH) Effect on GI: -↓1-hydroxylase activity

Calcium Deprivation Calcium Loading

Parathyroid hormone Secretion stimulated Secretion inhibited

Vitamin D Production stimulated by increased parathyroid hormone secretion

Synthesis suppressed due to low parathyroid hormone secretion

Calcitonin Very low level secretion Secretion stimulated high blood calcium

Intestinal absorption of calcium

Enhanced due to activity of vitamin D on intestinal epithelial cells

Low basal uptake

Release of calcium and phosphate from bone

Stimulated by increased parathyroid hormone and vitamin D

Decreased due to low parathyroid hormone and vitamin D

Renal excretion of

calcium

Decreased due to enhanced tubular reabsorption stimulated by elevated parathyroid hormone and vitamin D; hypocalcemia also activates calcium sensors in loop of Henle to directly facilitate calcium reabsorption

Elevated due to decreased parathyroid hormone-stimulated reabsorption.

Renal excretion of phosphate

Strongly stimulated by parathyroid hormone; this phosphaturic activity prevents adverse effects of elevated phosphate from bone resorption

Decreased due to hypoparathyroidism

General Response

Typically see near normal serum concentrations of calcium and phosphate due to compensatory mechanisms. Long term deprivation leads to bone thining (osteopenia).

Low intestinal absorption and enhanced renal excretion guard against development of hypercalcemia.

Summary

Bone Physiology Osteoblasts - build up bone secrete collagen = osteoid array of bone Osteocytes – bone cells Osteoclasts – resorb bone -use collagenase, hyaluronic acid, and acid phosphatase

-Bone remodeling necessary for bone strength Hydroxyapatite (Ca10(PO4)6(OH)2) = mineral part of bone Pathology Hypercalcemia Symptoms: -muscle weakness -CNS impairment -Ca++ precipitate on skin, kidney, joints -constipation, nausea vomiting Causes: -hyperparathyroidism (parathyroid tumor?) -pseudohyperthyroidism (kidney failure) -↓[Ca++] chronically causes overstimulation of parathyroids to make PTH

-Vit. D poisoning (taking too much in) Hypocalcemia Symptoms: -tetany(Trousseau’s sign, Chvostek’s sign) -paresthesias -hyperventilation -convulsions Causes: -hypoparathyroidism (accidental surgical removal) -pseudohypothyroidism (defective PTH receptor) -Vit. D deficiency -rickets in children -osteomalacia in adults -due to: -deficiency in Vit. D receptor -kidney failure →↓1,25-Vit. D prod. -↓absorption of Vit. D by GI -no sunlight w/o supplementation Osteoporosis Risk factors: -female -nonblack -short stature (less bone to begin with)

-post-menopausal (estrogen is lost after menopause, and E activates osteoblasts) -Cushing’s Disease Treatments: -exercise -ERT (but has ↑ risk of endometrial cancer) -bisphosphonates – Fosamax (“permanently” infuses bisphosphonate into bone) -calcitonin (refer to calcitonin’s “Effects on Bone”) -Ca++ + Vit. D -SERMs (raloxifene, tamoxifen – have estrogenic effects on bone)