Bone Physiology Michels Flashcards Preview

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Flashcards in Bone Physiology Michels Deck (93):
1

what are the major mineral components in bone

calcium and phosphorus

2

what three forms is extracellular calcium found in?

bound calcium -bound to albumin (40%) non diffusible

ionized calcium (50%) diffusible

remaining 10 percent is complexed with other anions (nonionized) (diffusible)

3

chemical gradient of ca between extracellular calcium and intracellular calcium

10,000:1 (favors calcium entry into cells)

4

hypocalcemia

nervous system becomes more excitable as serum calcium levels drop to a reduced activation threshold level for Na channels

5

tetany

contractions due to low calcium levels which causes subsequent reduced activation threshold level for Na channels

6

hypercalcemia

nervous system becomes depressed and reflex responses are slowed

also causes decreased QT interval of the heart, lack of appetite and constipation (due to decreased contractility of the heart and muscle walls of the GI tract)

7

Hypocalcemia (long explanation)

When the extracellular fluid concentration of calcium ions falls below normal, the nervous system becomes progressively more excitable because this causes increased neuronal membrane permeability to sodium ions, allowing easy initiation of action potentials. At plasma calcium ion concentrations about 50 percent below normal, the peripheral nerve fibers become so excitable that they begin to discharge spontaneously, initiating trains of nerve impulses that pass to the peripheral skeletal muscles to elicit tetanic muscle contraction. Consequently, hypocalcemia causes tetany. It also occasionally causes seizures because of its action of increasing excitability in the brain.

8

phosphates form in the serum

H2PO4- or HPO42-

9

concentration and function of extracellular calcium

total in serum 2.5x10-3 M

bone mineral
blood coagulation
membrane excitability

10

concentration and function of extracellular phosphate

total in serum 1.00 x10-3 M

bone mineral

11

concentration and function of intracellular calcium

10^-7 M

signal for:
-neuron activation
-hormone secretion
-muscle contraction

12

concentration and function of intracellular phosphate

1-2 x 10^-3

structural role
high energy bonds
regulation of proteins by phosphorylation

13

normal range of calcium in the extracellular space

8.5-10.5 mg/dL or 2.1-2.6 mM

14

control of calcium and phosphate in the extracellular space

PTH (parathyroid)
Calcitonin
calcitrol

fibroblast growth factor (phosphate only)

15

what regulates PTH release

regulated by ionized serum calcium levels and low levels trigger PTH release

16

Four functions of PTH

trigger the initiation of bone resorption leading to release of calcium into the serum

regulates calcium retention

regulates phosphate excretion in the kidney

increases synthesis of calcitrol--> leading to an increase in calcium absorption from the GI tract

17

where do PTH receptors reside

osteoblast cells

18

what happens with unregulated release of PTH

hypercalcemia

19

what produces Calcitonin

C cells in the thyroid gland

20

what is calcitonin released in response to....

released in response to elevated levels of serum calcium (inhibits osteoclast function)

***calcitonin is not necessary to maintatin normal ca levels in humans but levels of calcitonin rise in individuals with medullary thyroid cancer and other endocrine malignancies so it is a ***tumor marker***

21

calcitonin therapeutically?

treatment of bone disorders characterized by excessive bone resorption

22

where is the prohormone vitamin D converted to active form vitamin D

kidney

23

what is the function of calcitrol?

absorption of ca from the GI tract

bone formation

promotes both ca and phosphate resorption from the kidney

24

lack of vitamin D levels results in....

impaired Ca absorption and poor mineralization of bone b/c vitamin D is needed for calcitrol synthesis

also leads to increased phosphate secretion

25

Fibroblast growth factor does what?

phosphate regulation at the levels of the kidney

FGF23 usually results in downregulation of calcitrol levels (lowering ca absorption) and lowering levels of phosphate

26

absence of FGF23?

results in increased levels of phosphate and calcium due to increased levels of calcitrol

27

regulation of FGF23

under the control of dietary phosphorus, serum phosphorus and calcitrol levels (mechanism not really known)

28

trabecular bone

found on inside of long bones, the vertebrae and on large flat bones

metabolically active (more so than cortical bone)

29

cortical bone

dense and compact

80 percent of skeleton

strength and protection

rarely subject to metabolic processes (although it can be used)

30

inorganic matrix of bone

hydroxyapatite

trace amounts of Magnesium, Sodium, Potassium, Fluoride, Chloride

31

Organic part of bone (osteoid)

Cells --> osteoblasts, osteocytes, osteoclasts

Matrix-->
Collagen type I (90%)

Bone proteoglycan

Non-collagenous proteins
-osteocalcin
-osteonectin
-bone sialoprotein
-matrix GLA protein
-fibronectin

32

three principle amino acids of the collagen helix

glycine, alanine, proline and an unusual amino acid 4-hydroxyproline

33

primary unit of collagen?

single polypeptide --> alpha chain--> arranged in a left handed helix

34

why is glycine necessary in the collagen structure

it is the only aa that can accommodate the procollagen molecule

35

PINP

formed from cleavage of type I collagen to form larger collagen support structure

is the free amino-terminal

36

PICP

formed from cleavage of type I collagen to form larger collagen support structure

carboxy-terminal end

37

what can be measured in serum as a marker of collagen formation?

non-helical portions at the amino and carboxy terminals

38

what gives collagen its tremendous tensile strength

aligned tropocollagen molecules

39

what gives collagen its strength and flexibility

cross links b/w molecules of tropocollagen

in the bone these cross links consist of pyridinoline molecules (links form between hydroxylated lysine residues)

Absorbic acid is necessary for these cross-links!!!

40

Absence of ascorbic acid??

SCURVY

symptoms include:
small hemorrhages caused by fragile blood vessels
tooth loss
poor wound healing
reopening of old wounds
bone pain and degeneration
heart failure

41

The products of collagen breakdown that can be measured in serum/urine (5)

hydroxyproline
NTx
CTx
pyridinoline
deoxypridinoline

42

periosteal apposition

increase in bone width

during childhood this is accompanied by endosteal resorption or resorption of the bone surface in contact with the marrow cavity

43

bone remodeling is coupled meaning what?

bone resorption is followed by bone formation

44

osteoblasts are derived from what?

mesenchymal stem cells

45

what do osteoblasts do?

lay down collagen and noncollagen proteins prior to mineralization

46

why is mineralization delayed for several days

allows for collagen cross-linking

47

what is released during bone formation

bone specific alkaline phosphatase AND osteocalcin

these can be markers used to access bone formation

48

osteoclasts do what?

mediate bone resorption

how? through the secretion of proteases and hydrogen ions to lower the pH

49

what are osteoclasts derived from

hematopoietic stem cells and differentiate to form large multinucleated cells

50

what are the signals for osteoclast differentiation

derived from osteoblast cells in response to PTH stimulation

51

where is the receptor for calcitonin?

resides on osteoclast cells and is an INHIBITORY factor

52

connection b/w osteoblasts and osteocytes is important in what>

sensing mechanical stress within the bone, and this stress within the bone can be transmitted to the surface and the process of bone remodeling can be triggered

53

what does PTH do to osteoblasts?

stimulates them to release M-CSF

54

what does M-CSF do?

stimulates the differentiation of hematopoietic stem cells to osteoclasts precursors

55

RANK L

released by osteoblasts
triggers bone resorption by osteoclasts

56

RANK

receptor for RANKL

located on osteoclasts

57

IL-6

mediates bone resorption

58

OPG

after two weeks of activation (of osteoclasts) OPG terminates bone resorption by acting as a soluble receptor for RANKL thus inhibiting RANKL from binding RANK

59

disease states that are related to hyperactive and chaotic bone deposition result in ....

weakened bone

60

as people age what happens to bone resorption and bone formation?

process becomes uncoupled, usually leading to net bone resorption

61

Steps of bone remodeling

Activation
Resorption
Reversal
Formation

62

Glucocorticoids

retard bone formation

1) suppress intestinal calcium absorption and induce osteoclastogenesis

2) deplete osteoblasts through supppression of differentiation factors and induction of apoptosis

63

Gonadal hormones

estrogens and androgens

estrogens: needed for closure of epiphyseal plates
lack of estrogen during development results in increased adult height and decreased bone density
-decrease bone resorption (cytokines and prostaglandins)

androgens: increase bone formation

64

estrogen deficiency

results in loss of bone mass

65

cytokines do what to bone?

promote bone resorption

includes:
IL-6
RANKL and RANK
TNF alpha and beta
IL-1 alpha and beta

66

prostaglandins do what?

promote bone resorption

67

Growth factors that influence the balance between bone resorption and formation

FGF
PDGF
IGF
BMP's

68

how do we measure bone mass

bone mineral densitometry

this can determine if there is a loss of bone mass but NOT the cause

69

T scores

compare subject to young adult normal

70

Z scores

compare subject to age-matched normal

71

DEXA scanning

common method to measure bone densitometry

can be used to diagnose osteoporosis

72

WHO criteria

T-score > or equal to -1 is normal

T score between -1 and -2.5 is osteopenia

T score less than or equal to -2.5 osteoporosis

73

Biochemical measurements of bone formation

Alkaline phosphatase

Osteocalcin

Procollagen Peptides

74

Biochemical measurements of bone resorption

Urinary hydroxyproline

Collagen cross links (NTX or CTX)

75

true or false:
bone biopsies are not typically called for in pt's with osteoporosis

TRUE

76

primary osteoporosis

found in postmenopausal women and older men who do not have a definable secondary cause

77

secondary osteoporosis

can result from many factors

two examples include glucocorticoid excess and hypogonadism

78

treatment of osteoporosis?

Antiresorptive --> bisphosphonates

anabolic--> intermittent PTH injections

79

osteomalacia

rickets and osteomalacia are characterized by disorders in mineralization of the organic matrix through interrupted supply or transport of minerals in renal, intestinal or bone cell disorders

most often vit D deficiency

increased fracture risk

80

Paget's

characterized by excessive osteoblastic activity and hyperactive bone remodeling

commonly causes no symptoms

highly elevated phosphatase levels

81

common bones affected in Paget's

spine
femur
pelvis
skull
collar bone
humerus

82

symptoms of Paget's

fracture
arthritis
bone pain
deformity

tingling and numbness due to enlarged bones pinching nerves

limping

83

treatment of paget's

bisphosphonates

84

what stage is paget's typically diagnosed in?

sclerotic phase which is characterized by extremely high levels of alkaline phosphatase

85

stages of Paget's

osteolytic stage--> excess osteoclast

mixed phase--> both osteoclast and osteoblast

osteosclerotic phase--> predominant osteoblastic activity and marked sclerosis

86

osteogenesis imperfecta

brittle bone disease

weakening of bone due to mutations in collagen leading to bone fractures and deformity

87

OI type I

most common

autosomal dominant

one allele of the alpha 1 procollagen gene is missing
resulting in decreased collagen production but normal collagen structure

delayed fontanelle closure
bone fragility
short stature
blue sclerae
joint laxity
hearing loss
osteopenia of the long bones and wormian bones of the skull

88

OI type II

point mutation of COL1A1

extreme bone fragility and death intrauterine or early infancy secondary to respiratory deficiency

89

OI type III

similar to type II but less sever

skull deformities

90

OI type IV

similar to type I but less severe

91

osteopetrosis

marble bone disease

defective osteoclastic bone resorption and disorganized bone structure resulting in weakened bone and increased fracture risk

due to genetic mutations

92

bisphosphonates

inhibit osteoclast activation

93

prolia

denosumab monoclonal antibody directed against RANKL

inhibits bone resorption