SM160 Calcium/PTH/Bone Pharm

Question 1

Normal serum calcium

Answer 1

8.5-10.5 mg/dL

Question 2

Calcium forms in blood

Answer 2

50% ionized (active), 10% bound to anions, 40% protein bound

Question 3

Active form of vit. D? Storage form?

Answer 3

Active: calcitriol - 1,25(OH)2D3
Storage: cholecalciferol/calcidiol - 25(OH)D3

Question 4

Where is calcium absorption vit. D dependent?

Answer 4

Proximal duodenum

Question 5

What type of diuretic gives you hypocalcemia and what type gives you hypercalcemia?

Answer 5

Loops cause hypocalcemia, thiazides cause hypercalcemia

Question 6

PTH actions on kidney

Answer 6

Increased calcium absorption, potassium loss, stimulates 1alpha-hydroxylase

Question 7

Calcium form in bone

Answer 7

Hydroxyapatite: Ca10[PO4]6[OH]2

Question 8

Cell lineage of osteoclasts

Answer 8

Monocyte (related to macrophages)

Question 9

Osteoclast differentiation

Answer 9

Osteoblasts express RANK-L, which stimulates osteoclasts and osteoclast precursors via the RANK receptor

Question 10

Osteoprotegerin

Answer 10

RANK-L antagonist produced by osteoblasts, ratio of RANK-L to osteoprotegerin is important

Question 11

Osteoclast action

Answer 11

Resorb collagenous bone matrix by secreting acid and proteases

Question 12

Osteoblast action

Answer 12

Produces alkaline phosphatase (elevation indicates active osteoblasts), collagen (combines with hydroxyapatite to form bone), osteocalcin

Also promotes osteoclast differentiation, survival, and activity via RANK-L

Question 13

Osteoblast stimulants

Answer 13

IGF-1, bone morphogenetic proteins, wnt signaling pathway

Question 14

Osteocyte actions, effect on osteoblasts

Answer 14

Sense mechanical load

Produce sclerostin to inhibit wnt signaling and osteoblast differentiation (if you could block this you could stimulate bone formation)

Question 15

Osteoporosis

Answer 15

Systemic condition in which osteoblastic activity can’t keep pace with osteoclastic activity

Results in loss of mineral and matrix, susceptibility to fracture

Question 16

Paget’s disease of bone

Answer 16

Locally increased osteoclast activity is followed by increased osteoblast activity

Results in abnormal bone formations

Question 17

Vit. D synthesis

Answer 17

Starts with cholesterol, turned into Vit. D3 in skin (cholecalciferol - UVB light required), D3 is converted into 25(OH)D (calcidiol) in the liver and then into 1,25(OH)2D3 (calcitriol) in the kidney by 1a-hydroxylase

Question 18

Vit. D/calcitriol actions

Answer 18

Stimulates intestinal Ca++ and phosphate absorption in the proximal duodenum, blocks PTH

Question 19

Disease of deficient vit. D? Excess vit. D?

Answer 19

Deficiency: rickets and osteomalacia
Excess: hypercalcemia, osteoclastogenesis

Question 20

Indications for calcitriol and different forms available

Answer 20

Alphacalcidol: secondary hyperparathyroidism resulting from renal disease and impaired renal 1-hydroxylation (doesn’t require hydroxylation)

Calcipotriol (topical): proriasis

(Last 3 are in learning guide, not in slides)
Ergocalciferol: hypocalcemia, rickets, osteomalacia, hypoparathyroidism

Doxercalciferol: secondary hyperparathyroidism

Paracalcitol and 22-oxocalcitriol: suppress PTH with minimal effects on Ca and P, used for secondary hyperparathyroidism

Question 21

Vit. D/calcitriol pharmacokinetics

Answer 21

Oral, bound to alpha-globulin, inactivated by kidney, hepatic elimination

Question 22

Vit. D/calcitriol major side effect

Answer 22

Hypercalcemia

Treatment: stop drug, low calcium diet, glucocorticoids, fluids

Question 23

PTH generic drug name

Answer 23

Teriparatide

Question 24

What can suppress PTH?

Answer 24

Calcium (+ calcimimetics) via CaSR and vit. D (calcitriol)

Question 25

Cinacalcet: drug type, mechanism, indication, side effects

Answer 25

Calcimimetic Activates CaSR to suppress PTH secretion Hyperparathyroidism Hypocalcemia, adynamic bone disease

Question 26

PTH actions on bone: continuous exposure vs. intermittent exposure

Answer 26

Continuous exposure: bone loss due to increased RANK-L expression Intermittent exposure: bone formation from decreased osteoblast apoptosis, increased osteoblast differentiation, and sclerostin suppression

Question 27

Teriparatide: use, limitations

Answer 27

Osteoporosis | Hypercalcemia and osteosarcoma risk (though not yet seen in humans)

Question 28

PTHrP

Answer 28

Associated with hypercalcemia seen in malignancy

Question 29

Calcitonin: mechanism, use, limitations

Answer 29

Acts on mature osteoclasts via GPCR to inhibit bone resorption Paget's disease, hypercalcemia, and a minor role for osteoporosis Low efficacy, can't give orally, resistance develops

Question 30

Calcitonin-gene related peptide (CGRP): action, use

Answer 30

Potent vasodilator | Migraines

Question 31

Estrogen actions on bone

Answer 31

Inhibits bone resorption: less IL-6, more osteoprotegerin (RANK-L antagonist), more apoptosis of osteoclasts

Question 32

Glucocorticoids influence on calcium

Answer 32

Blocks absorption in the gut, block reabsorption in the kidney. Long-term can cause osteoporosis.

Question 33

FGF-23: what secretes it, action

Answer 33

Secreted by osteoblasts and osteoclasts in response to elevated calcitriol Increases phosphate excretion in the kidney

Question 34

Estrogen use, role of progestin?

Answer 34

Prevention of postmenopausal bone loss | Progestin helps to prevent uterine hyperplasia and malignant changes

Question 35

Role of androgens in bone health

Answer 35

Androgens are aromatized to estrogen in bone, men with aromatase deficiency can get osteoporosis

Question 36

Raloxifene: drug type, mechanism, indications, side effects

Answer 36

SERM (selective estrogen response modulator) Mechanism: estrogen agonist in bone, antagonist in breast Uses: prevent postmenopausal osteoporosis and reduce the risk of bone metastasis from breast cancer Side effects: thromboses and hot flashes Contraindication: women that want to get pregnant

Question 37

Bisphosphonates: examples, mechanism, uses, side effects

Answer 37

Alenodrate (plus other -dronates), zoledronic acid Pyrophosphate analogs, bind hydroxyapatite in bone, inhibit osteoclast activity Paget's, osteoporosis, hypercalcemia, bone metastases GERD, esophageal irritation, osteonecrosis of the jaw

Question 38

Denosumab: mechanism, actions, use, side effects

Answer 38

Monoclonal Ab against RANK-L Inhibits osteoclast differentation, function, and survival, increasing bone mineral density Uses: osteoporosis, bone metastases Side effects: hypocalcemia, rash, osteonecrosis of the jaw, immunosuppression

Question 39

What is the only currently used anabolic therapy for osteoporosis?

Answer 39

Teriparatide (PTH)