calcium (PTH) homeostasis

what's the relationship between PTH and Ca?

*very tightly regulated*

1. Which of the following statements is TRUE? a. The largest fraction of total body calcium is found in the plasma. b. Approximately 50% of plasma calcium is in the free, or ionized form. c. Free plasma calcium would be decreased by severe acidosis. d. Most of the calcium that we ingest is absorbed in the GI tract. e. To maintain calcium balance in a healthy individual, the daily rate of renal calcium excretion must equal the daily rate of net plasma calcium increase from bone resorption.

1. b

10. Hypocalcemia might result in all of the following EXCEPT: a. Osteomalacia b. Rickets c. Tetany d. Kidney stones e. Trousseau's sign

10. d

2. Which of the following would you expect to find in a patient whose diet has been low in calcium for the past 2 months? a. Increased formation of 24, 25-dihydroxy vitamin D3 b. Decreased amounts of calcium binding protein in intestinal epithelial cells c. Increased parathyroid hormone secretion d. A high plasma calcitonin concentration e. Increased plasma phosphate levels

2. c

3. In primary hypoparathyroidism, plasma levels of PTH, calcium and phosphate would be: a. High PTH, high Ca, low phosphate b. High PTH, low Ca, high phosphate c. High PTH, low Ca, low phosphate d. Low PTH, low Ca, high phosphate e. Low PTH, low Ca, low phosphate

3. d

4. Vitamin D3 toxicity would be associated with the following plasma profile: a. High PTH, high Ca, low phosphate b. High PTH, low Ca, high phosphate c. High PTH, low Ca, low phosphate d. Low PTH, low Ca, high phosphate e. Low PTH, high Ca, high phosphate

4. e

5. Bone resorption would be elicited by: a. Increased activation of PTH receptors on the osteoclasts b. Increased release of osteoprotegrin by the osteoblasts c. Increased binding of RANK to RANKL d. Decreased activation of osteoclastic cytokine receptors e. An increase in osteoclast apoptosis

5. c

where is body calcium located?

50% of calcium in plasma is in *free form* - most important - only portion regulated by hormones

6. Which of the following is TRUE regarding the synthesis of active vitamin D3? a. Ultraviolet radiation of the skin catalyzes formation of 25-hydroxy-D3. b. Three organ systems are required: skin, bone and kidney. c. The active hormone requires hydroxylation at positions 1 and 24. d. 24-hydroxylation takes place in the liver. e. PTH regulates the 1-hydroxylation step that occurs in the kidneys.

6. e

7. Calcitonin a. Binds to its receptors on the osteocytes. b. Is synthesized and secreted by the parathyroid glands. c. Release is stimulated by TSH. d. Can be used clinically to prevent osteoclastic bone resorption. e. Must be replaced after thyroidectomy to maintain normal calcium balance.

7. d

8. All of the following might be observed in a patient with hypercalcemia EXCEPT a. Anorexia b. Kidney stones c. Personality changes d. Bone fractures e. Trousseau's sign

8. e

9. Which of the following is NOT TRUE of the actions of estradiol in bone? a. In early puberty, causes the increase in growth in the long bones of both males and females. b. Acts via estrogen receptors in females, and androgen receptors in males. c. At the higher adult circulating levels, causes epiphyseal closure. d. Throughout life, stimulates osteoblast proliferation. e. Decreases with age in men and women, resulting in osteoporosis.

9. b

4. Describe the sequence of events and sites involved in 1,25 dihydroxy D3 metabolism. Which step is the control point in this pathway?

A pre-vitamin is converted to vit D by the action of UV light and heat on the skin. The vit D circulates in plasma. In the liver, it is converted to 25-OH- D, which also circulates in plasma. In the kidney, this compound is either 1-hydroxylated to 1,25-(OH)2 D, the active form, or *24, 25-(OH)2 D, an inactive form*. The control point for these reactions is in the kidney.

6. Although calcitonin plays a minimal physiological role in calcium homeostasis, this hormone has several clinical uses. What are they?

Calcitonin is used clinically to decrease osteoclast activity, and thus bone resorption in Paget's disease of the bone. It can be used as an acute treatment for hypercalcemia. It also has analgesic properties, and is a marker for medullary cancer of the thyroid.

7. A patient presented with osteomalacia, low plasma calcium levels, high circulating PTH, and elevated 1,25 dihydroxy D. What might be the cause of the osteomalacia? Explain the reason for your answer.

Decreased vitamin D receptors or defective vitamin D receptors, or a post-receptor defect. In a child, this would cause rickets. The low calcium is stimulating PTH release, but the high PTH is not able to elevate calcium levels. In view of the elevated vitamin D levels, which would be stimulated by the high PTH, this suggests that PTH is acting normally but there is a defect in response to vitamin D. Another possibility is chronic low calcium intake due to poor diet, or malabsorption in the GI tract due to other causes than low vitamin D.

3. Compare the plasma levels of PTH, calcium and phosphate in hyperparathyroidism and vitamin D toxicity. Explain the differences from normal based on the physiological mechanisms controlling calcium homeostasis.

In the presence of excess PTH due to hyperparathyroidism, plasma Ca will be high due to increased bone resorption, vit D metabolism, and gut absorption. In addition, renal Ca reabsorption will be increased, along with phosphate excretion, leading to lower plasma phosphate levels. Excess vitamin D would cause excessive Ca absorption from the gut, and enhance bone resorption, thereby elevating plasma Ca levels. This in turn would suppress PTH levels, thereby decreasing renal phosphate excretion and causing high plasma phosphate levels.

5. Discuss the controls of renal 1-hydroxylase and 24-hydroxylase activity.

Increased 1,25 dihydroxy D3 or plasma phosphate levels inhibit the 1-hydroxylase and stimulate the 24-hydroxylase, whereas increased plasma PTH concentrations stimulate the 1-hydroxylase and inhibit 24-hydroxylase activity.

8. What are the differences between osteocytic osteolysis and osteoclastic resorption in time of onset and mechanisms? What controls these processes?

Osteocytic osteolysis - rapid; only calcium is released from bone fluid; osteocytes Osteoclastic resorption - slow; longer latent period; both calcium and phosphate are released from bone mineral; osteoclasts PTH increases both of these processes

what are some causes (4) of hypocalcemia?

PTH normally ^ Ca and dec P note Li can increase VD3 conversion to inactive form 1-OHase activity is increased by PTH and decreased by P

1. Why are PTH levels increased in rickets (vitamin D deficiency)?

Rickets is a disease occurring in children that is characterized by a *deficiency in vitamin D3*. In the absence of adequate D3 absorption of Ca in the gut is impaired. In addition, the action of PTH in bone resorption is not optimal in the absence of vit D. These effects of lowered vit D will eventually lead to a decrease in plasma Ca, which will in turn trigger an increase in PTH secretion.

9. What other hormones can affect bone growth and remodeling and how?

Sex steroids, estradiol and testosterone, which gets converted to estradiol in the bone cells. Estradiol protects against bone resorption via several mechanisms. Cortisol and thyroid hormones are important at normal levels for normal bone growth and remodeling, but at high levels they can cause osteoporosis. Loss of estradiol after menopause in females, and throughout life after about 30 years of age in both sexes, leads to osteoporosis. See the lecture notes for further details.

2. Compare the plasma levels of PTH, calcium and phosphate in hypoparathyroidism, pseudohypoparathyroidism, and rickets. Explain the differences from normal based on the physiological mechanisms controlling calcium homeostasis.

When PTH secretion is low, as in hypoparathyroidism, bone resorption is decreased, vit D synthesis is decreased, and as a result, gut absorption of Ca is low, thus leading to low plasma Ca levels. Decreased PTH levels also diminish renal phosphate excretion, therefore plasma phosphate levels will be increased. In cases of pseudohypoparathyroidism, *PTH receptors are defective*, therefore PTH cannot increase bone resorption, vit D synthesis, or renal Ca reabsorption or phosphate excretion. This leads to low plasma Ca and high plasma phosphate. The low Ca stimulates PTH release, thus leading to an abnormally high plasma PTH level in the presence of low Ca.

how do estradiol and testosterone affect calcium?

estradiol is protective of bone

what are some causes (3) of hypercalcemia?

excess intake --> feedback to drop PTH, increasing P PTHrP --> increase Ca and dec. P, and will suppress endogenous PTH

where does Ca reabsorption occur in the kidney? - what hormone increases this?

fine tuning of Ca levels occurs at distal nephrons

why is bone remodeling important? describe step 1: activation of osteoclasts?

helps maintains Ca2+ levels in the plasma

why is calcium homeostasis important: - intracellularly - in plasma?

if Ca2+ gets too low, can lead to tetany --> death

what are some other (6) causes of bone loss?

kids aren't exercising as much as they should --> lower peak bone mass drugs block absorption of Ca in gut and convert VD3 to inactive form

what are the two pools of Ca in bone?

osteocytic osteolysis transfers Ca from bone fluid --> plasma - triggered via mechanical stress (i.e. exercise)

describe parathyroid hormone. how does it impact calcium levels?

receptors are *not on osteoclasts*, but on osteoblasts and cytes

describe Ca exchange in the GI tract - _____ regulates Ca uptake in the gut?

vitamin D3 controls Ca uptake in the gut

what are the actions of PTH and active vitamin D3?

when PTH is active in kidneys, Ca is resorbed while P is excreted to prevent solute precipitation

describe bone remodeling steps 3, 4: reversal and bone formation?

whole thing takes 2 - 4 months long cannot have formation without resorption