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Pharmacology III > Exam 2- Bone > Flashcards

Exam 2- Bone Flashcards

1
Q

Function of bone (3)

A
  • structural support and protection
  • hematopoiesis (formation of immune cells)
  • mineral storage
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2
Q

Inorganic component of bone

A
  • hydroxyapatite
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3
Q

Calcium’s role in the body (3)

A
  • neurotransmitter release-
  • muscle contraction
  • coagulation
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4
Q

Phosphate’s role in the body (3)

A
  • ATP, DNA, RNA
  • cellular signaling (kinase cascades)
  • Phospholipids
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5
Q

Bone Architecture: 2 types

A
  • long bone

- vertebral bones and in the neck/head of femur

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6
Q

Long bone

A
  • cortex and medulla
  • cortex: forms thick outer layer
  • medulla: trabecular bone (ends, spongy) and bone marrow
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7
Q

Vertebral bones and in the neck/head of femur

A
  • cortical bone forms a thinner layer surrounding a larger core of trabecular bone
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8
Q

most remodeling is in which part of the bone?

A
  • trabecular (almost exclusively)
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9
Q

Bone composition

A
  • 75% inorganic components (primarily hydroxyapatite)
  • 99% of the body’s calcium is stored in skeleton
  • 25% organic components
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10
Q

Organic components of bone

A
  • Cells (osteoblasts, osteoclasts, osteocytes) (bone lining cells)
  • Osteoid (matrix consisting primarily of type I collagen fibers; other low-abundance proteins)
  • Growth factors (as you break down bone, growth factor is released)
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11
Q

Average daily intake of Ca vs absorption and what is done with the balance

A
  • daily intake 1000mg
  • 300 mg dietary Ca normally absorbed
  • balance excreted in feces and urine
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12
Q

Calcium is absorbed where and how transported?

A
  • Small intestine
  • facilitated transport throughout small intestine
  • Vitamin D dependent transport mainly in duodenum
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13
Q

If defects/deficiencies in Vitamin D, what happens to Ca?

A
  • not enough is absorbed
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14
Q

Calcium absorption can be increased to 600 mg/day by ______

A
  • calcitrol (active form vit D)
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15
Q

% of trabecular and cortical bone remodeled each year in adults? What does this mean in regards to deficiencies in calcium?

A
  • 25% of trabecular bone remodeled each year
  • 3% of cortical bone
  • If there is a deficit, within a year will see deficiency in density of bone
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16
Q

pathological conditions preferentially affect bones with high content of ______

A
  • trabecular bone

- ex femoral neck and vertebral bodies

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17
Q

osteocytes’ job

A
  • sense stress, regulate activity of osteoclasts and osteoblasts (slide 19)
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18
Q

Bone Resorption

A
  • physical or chemical signals recruit osteoclasts
  • excavate small cavities on surface of bone
  • extend villus-like projections towards bone surface that secrete proteolytic enzymes that digest the organic matrix
  • create an acidic microenviron by producing organic acids (H/ATPase pump on surface of villi) which dissolves hydroxyapatite
  • lasts about three weeks which at that point cytokines and other factors are liberated from the matrix to stim bone formation
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19
Q

Bone Formation

A
  • osteoblasts replace osteoclasts in the resorption cavity
  • begin to refill the cavity with concentric layers of unmineralized organic matrix (osteoid/lamellae)
  • eventually the osteoblasts become completely surrounded with matrix –> become osteocytes
  • osteocytes act as mechanosensors in bone
  • Osteoblasts secrete factors for mineralization
  • Alkaline phosphatase
  • Calcium-binding proteins
20
Q

What does alkaline phosphatase do in the process of bone formation?

A
  • hydrolyzes various phosphate esters including pyrophosphate which is an inhibitor of bone mineralization
  • promotes crystallization of calcium phosphate salts
21
Q

What do calcium-binding proteins do for bone formation?

A
  • increase local concentration of calcium

- facilitates hydroxyapatite formation

22
Q

Parathyroid hormone and it’s secretion

A
  • secreted by parathyroid glands
  • most important endocrine regulator of calcium homeostasis
  • secretion regulated by plasma calcium levels
  • calcium-sensing membrane receptors of chief cells in Parathyroid gland
  • GPCRs cause increased intracellular free calcium
  • Increased intracellular calcium levels DECREASES secretion of preformed PTH
  • decreased intracellular calcium levels INCREASES secretion of preformed PTH
  • this is opposite of most secretory systems
23
Q

PTH receptor Activation (two main types/groups of receptors and where they are expressed)

A
  • PTH/PTHrP receptor
  • responds to PTH and PTH-related protein
  • expressed high levels in kidneys and osteoBLASTS
  • activates several G proteins
  • PTH2 receptor
  • activated by PTH but not PTHrP
  • expressed in brain, vascular endothelium, smooth muscle, GI endocrine cells, sperm
  • functional role is unknown
24
Q

Effects of PTH on kidney

A
  • Direct
  • most rapid physiological effects of PTH
  • increases reabsorption of calcium by kidney (decreases urinary excretion)
  • Decrease reabsorption of phosphate by kidney (increases urinary excretion)
  • PTH raises plasma calcium levels and decreases plasma phosphate concentrations
25
Q

Effects of PTH on bone

A
  • Direct
  • slower effect of PTH than kidney
  • physiologic levels of PTH stim cell surface PTH receptors on osteoBLASTS
  • causes increased expression of RANK-L
  • liberates calcium and phosphate by osteoclastic activity
  • raises plasma calcium levels
26
Q

What does RANK-L do?

A
  • RANK-L is expressed on osteoBLASTS and binds to RANK on osteoCLAST precursor cells in bone marrow
  • this binding promotes differentiation into mature osteoCLASTS
  • this then liberates calcium and phosphate by osteoclastic activity
27
Q

Effects of PTH on GI tract

A
  • INDIRECT
  • PTH stims kidney which increases formation of calcitriol
  • hydroxylation step occurs in cells of proximal tubule
  • calcitriol increases calcium absorption in the small intestine
28
Q

Anabolic Actions of PTH

A
  • brief 1-2 hr exposure of PTH
  • increases bone formation and bone mass
  • enhances osteoblast survival and promotes osteoblast differentiation
  • Galphas receptor stimulation by mature osteoBLASTS increases cAMP which has an anti-apoptotic effect on osteoblasts and promotes osteoblasts IGF-1 release inducing osteoblast differentiation
  • PTH also induces production of cytokines by stromal cells which stims osteoCLAST production
  • but acutely osteoBLAST effect dominates
29
Q

Catabolic Actions of PTH

A
  • continuous exposure to PTH
  • mature osteoblasts stim production of IGF-binding proteins which decrease IGF-1 levels and osteoblast differentiation
  • PTH induces expression of osteoclast differentiation factors
  • net result is osteoCLASTS outnumber osteoBLASTS
30
Q

Vitamin D

A
  • produced in sufficient amts by the body (not usually needed through diet)
  • Vit D applies to 2 related compounds (equal biological activities)
  • Cholecalciferol (Vit D3): synthed by skin from exposure to UV radiation
  • Ergocalciferol (Vit D2): form produced by plants, what is present in many commerical preps and added to milk
31
Q

Calcitriol biosynthesis

A
  • active form of Vit D
  • Vit D2 and D3 travel to liver where it is stored or converted to calcifediol
  • two enzymatic hydroxylation steps to form calcitriol (second hydroxylation is PTH-dependent and in proximal tubule of kidney)
32
Q

Calcitriol: What it do

A
  • increases absorption of dietary Ca
  • acts on nuclear receptors in the enterocytes
  • up-regulates gene expression of certain Ca pumps and Ca binding proteins (calbindin)
  • inhibits PTH synth and release from parathyroid gland
  • increases osteoclast number and activity in bone
  • calcitriol affects distal tubule of kidney to increase reabsorption of both calcium and phosphate
  • macrophages can produce calcitriol
  • may act as a local suppressant of adaptive immune cells
33
Q

What can you use to treat psoriasis?

A
  • Vit D
34
Q

Calcitonin

A
  • produced and released by parafollicular C cells of thyroid gland
  • released in response to HYPERcalcemia
  • effects: binds directly to receptors on osteoCLASTS and inhibits the resorptive activity –> decreases bone resorption and plasma calcium levels
  • In adult humans: only weak effect of endogenous calcitonin on plasma calcium levels
  • thyroidectomy generally doesn’t cause any significant changes in plasma calcium levels
  • exogenous calcitonin used in treatment of osteoporosis
35
Q

Glucocorticoids and effect on bone processes

A
  • decreases intestinal absorption and tubular reabsorption of calcium, but NOT associated with hypocalcemia
  • compensatory increase in PTH
  • glucocorticoid effects on bone
  • inhibit osteoBLAST maturation
  • inhibit osteoBLAST activity
  • promotes osteoBLAST apoptosis
  • prolonged administration causes iatrogenic osteoporosis
36
Q

Thyroid hormone effect on bone processes

A
  • excess hormone increases bone turnover
  • stimulates bone resorption more than bone formation
  • prolonged elevated levels causes osteopenia
37
Q

Estrogens and androgens effect on bone processes

A
  • exert inhibitory effects on osteoCLASTIC activity
  • slow rate of bone turnover and bone loss
  • gonadal steroids inhibit the production of cytokines by osteoblasts (IL-6 normally recruits and activates osteoCLASTS
  • estrogen has pro-apoptotic effect on osteoclasts, anti-apoptotic effect on osteoblasts and osteocytes
38
Q

Osteoporosis general considerations and vs osteopenia

A
  • osteoporosis: decreased production of bone matrix and decreased BMD
  • Normal BMD: value within 1 SD of the mean BMD in young adults
  • Osteopenia: 1-2.5 SDs below the mean
  • Osteoporosis: >2.5 SDs below the mean
  • leads to increased risk of fracture from minimal trauma
  • esp vertebrae, femoral neck (hip), and radius (Colles’ fracture)
39
Q

Two categories of osteoporosis (list)

A
  • Primary (Senile and Post-menopausal)

- Secondary (systemic illness and medications induced)

40
Q

Senile Osteoporosis

A
  • peak bone mass achieved in young adulthood
  • determined by several factors: dietary calcium, Hormonal state, physical activity levels, genetic factors
  • gradual decline in bone mass during mid- late adult life
  • osteoblast-mediated bone formation declines in relation to osteoclast activity
  • average loss of 0.7% bone mass / year
41
Q

Postmenopausal Osteoporosis

A
  • begins in first 3-5 yrs after menopause
  • RAPID loss in bone mass related to marked decline in estrogen production
  • longer lifespan in osteoCLASTS in absence of estrogen
  • excavate deeper cavities which coalesce to form porous spaces in cortical bone
  • increased apoptosis of osteoblasts
  • increased apoptosis of osteocytes impairing mechanosensory network
  • within 25-35 yrs after menopause
  • 35% of cortical bone mass loss possible
  • 50% of trabecular bone mass loss possible
42
Q

Secondary Osteoporosis

A
  • systemic illnesses and medication-induced
  • common predisposing causes: Thyrotoxicosis, hyperparathyroidism, high doses glucocorticoids, smoking, alcohol abuse
  • treat UNDERLYING cause
43
Q

How does CKD affect bone mineral homeostasis?

A
  • mainly through secondary hyperparathyroidism which enhances resorption of bone
  • bones develop osteomalacia (decreased mineralization) and osteitis fibrosa cystica (increased osteoclastic resorption of bone with replacement by fibrous tissue)
44
Q

Hyperparathyroidism and CKD

A
  • decreased production of Calcitriol b/c impaired hydroxylation step in kidneys
  • results in HYPOcalcemia
  • results in HYPERphosphatemia (impairment of renal tubular function)
45
Q

Effects of low calcitriol with CKD

A
  • leads to inadequate intestinal absorption of calcium which leads to hypocalcemia
  • this stims PTH secretion and suppresses PTH degradation
  • reduces Ca receptor synth in chief cells of parathyroid gland which raises set point for Ca regulation (higher [Ca} required to suppress PTH)
  • hyperparathyroidism can persist even with hypercalcemia
  • low Ca levels cause SECONDARY hyperparathyroidism
  • Calcitriol also normally suppresses growth of the parathyroid gland and suppresses transcription of the PTH gene
  • HYPERphosphatemia results from the decreased renal excretion of phosphate, exacerbates the hypocalcemia, alters the equilib for hydroxyapatite formatino and dissolution
46
Q

Therapeutic treatment for CKD

A
  • active Vit D analogues (bypass hydroxylation requirement by kidneys)
  • calcimimetic cinacalcet (adjusts sensitivity of calcium-sensing receptor on parathyroid chief cells)

Pharmacology III (18 decks)

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