1. Endocrine Control of Calcium Levels Distribution of Ca+2 in body: Bones and teeth = 99% Soft tissues = 0.9% ECF = 0.1% Protein bound = 0.05% Free Ca+2 = 0.05% Only the 0.05% that’s free in the ECF is regulated, but it’s regulated closely. Three hormones are involved: Parathyroid hormone Calcitonin Vitamin D

2. Why is Regulation of Free Ca+2 Important? Most important is immediate effect on neurons and muscle cells. Hypocalcemia -> Hyperexcitability of both -> spastic contractions, even death from respiratory arrest Hypercalcemia -> Cardiac arrhythmias, depressed activity of nerves and muscles

3. Balance of Free Ca+2 in ECF Outputs: Renal excretion Deposition in bones and teeth Inputs: Absorption from gut Dissolution of bones and teeth Therefore, possible sites of endocrine control are: 1.Renal excretion 2.Deposition and dissolution of bones and teeth 3.Absorption from gut All three are under endocrine control.

4. Long and Short Term Regulation Rapid adjustments occur via effects on bones and teeth Long term regulation is via effects on renal excretion of Ca+2 Note similarities to long and short term regulation of body water (hence, arterial pressure) and plasma H+ concentration. Long term fine adjustments are renal.

5. Parathyroid Hormone Peptide hormone secreted by parathyroid gland. Has effects on bone deposition/dissolution, renal excretion of Ca+2 and intestinal absorption of Ca+2 Overall effect is to increase free Ca+2 in plasma

6. Parathyroid Hormone is Secreted by Parathyroid Glands Parathyroid glands are four lobes, each about the size of a grain of rice, on the posterior surface of the thyroid.

7. Bone Remodeling “Bony” part of bone consists of a collagen matrix with calcium phosphate deposited on it. This is what makes it rigid. The calcium phosphate is constantly being dissolved and re- deposited. Dissolution is more or less random, deposition is preferential along lines of stress and compression. This results in bones thickening along lines of stress and compression, called remodeling. That’s why broken bones heal and actually strengthen over time.

8. Bone Healing Two pairs of fractures, eight years apart.

9. Parathyroid Effects on Bone PTH -> rapid loss of Ca+2 from bones into plasma. Phosphate is released as well. This raises plasma calcium and phosphate levels, decreases bone density. Therefore, chronic conditions that would reduce plasma calcium levels result in weakened bones. Complication: raising calcium and phosphate in plasma can cause crystals to precipitate. Not good. Happily, PTH also effects kidneys.

10. Parathyroid Effects on Kidney PTH -> increased renal reabsorption of Ca+2, increased renal secretion of phosphate. Therefore, plasma Ca+2 level goes up, plasma phosphate level falls. Product of concentrations of calcium and phosphate remain constant, and precipitation of crystals is avoided.

11. Parathyroid Effects on Calcium Absorption Effect of PTH is indirect. Vitamin D activation is required for intestinal absorption of calcium. I’ll come back to that.

12. Control of PTH Secretion PTH secretion is stimulated by reduced plasma Ca+2 levels, inhibited by elevated plasma Ca+2 levels. There are no other controls on PTH secretion. No neural, no endocrine factors.

13. Calcitonin Peptide hormone produced by C cells in thyroid; sometimes called thyrocalcitonin. Decreases rate of bone reabsorption, tending to decrease plasma Ca+2 levels. Doesn’t seem to be very important except during periods of high Ca+2 demand, like lactation. Control of secretion is simple negative feedback loop: high plasma Ca+2 levels stimulate secretion, low plasma Ca+2 levels inhibit secretion.

14. Vitamin D Derivative of cholesterol; fat-soluble. Two sources: 1.Synthesis by skin exposed to sunlight. Rarely adequate except in tropical climates or during warm (sunny) seasons. Dark skin pigments reduce this source as well. 2.Dietary intake. Milk usually has vitamin D added, but there are lots of other sources in a balanced diet. Whatever the source, vitamin D doesn’t do anything until it’s “activated”. Activated vitamin D is required for Ca+2 absorption in the gut.

15. Activation of Vitamin D Two step conversion from vitamin D to activated vitamin D: First step occurs in liver; Second step occurs in kidneys. PTH promotes this step.

16. Overall System for Maintaining Normal Plasma Ca+2 If plasma Ca+2 falls, PTH secretion increases. This stimulates bone dissolution, releasing Ca+2 and phosphate into plasma. PTH also stimulates renal reabsorption of Ca+ and renal secretion of phosphate. PTH also stimulates activation of vitamin D, promoting intestinal absorption of Ca+2. Net effect of a chronic Ca+2 deficiency is that plasma levels are maintained at the expense of bone density.

17. Osteoporosis After about age 50, bone deposition during remodeling decreases. This results in loss of bone density, called osteoporosis. Plasma Ca+2 and phosphate levels are usually normal. Much more common in women than in men, so estrogens are probably important in preventing it. Exercise, adequate intake of Ca+2 and vitamin D while younger probably reduce osteoporosis because bones are denser before reduction in density begins. Exercise in old age is probably useful as well, because it adds stress and compression to bones.

18. Disorders involving PTH Hyperparathyroidism (usually from a PTH secreting tumor) results in symptoms related to elevated plasma Ca+2 levels: Muscle weakness (including cardiac muscle) Depressed neural activity (-> depression, memory loss, etc.) Bone fragility due to loss of calcium phosphate from bones Kidney stones as calcium phosphate precipitates in ureters Hypoparathyroidism (pretty rare) Muscle hyperexcitability (-> spasms, twitches) Hyperexcitability in nerves (-> tingling sensations and irritability) Total absence of PTH -> death from spastic contraction of respiratory muscles

19. Disorders Involving Vitamin D Vitamin D deficiency -> reduced ability to absorb Ca+2 from intestine. This reduces bone density in adults, reduces bone calcification in children. Vitamin D deficiency in children = rickets. Typically, legs bow under weight of body, along with other deformations