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Block 4 Week 1 Meg > Bone Metabolism and Osteoporosis > Flashcards

Bone Metabolism and Osteoporosis Flashcards

1
Q

Two most important minerals for cellular function.

A

calcium

phosphate

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2
Q

Approximately what percentage of calcium and phosphorous are in bone?

A

98% of calcium

85% of phosphorous

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3
Q

What can abnormalities in bone metabolism lead to?

A

wide variety of cellular dysfunction
defects in structural support
loss of hematopoietic activity

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4
Q

How much total calcium is present in bone?
How much of this is protein bound?
How much is ionized?

A

2.5mM; 40% protein bound; 50% ionized

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5
Q

What happens when there is a fall in plasma calcium concentration?

A

a fall in plasma calcium leads to secretion of PTH from the parathyroid which stimulates conversion of calcifediol to calcitriol which causes increased calcium absorption from intestine, decreased excretion from the kidneys, and increased mobilization from bone to ultimately increase plasma calcium levels

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6
Q

What two things does calcitonin do to decrease blood calcium levels?

A

prevents the kidneys from “decreasing excretion” and decreases mobilization of calcium from bone

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7
Q

3 hormones serve as the principle regulators of calcium and phosphate. What are they?

A

parathyroid hormone
fibroblast growth factor 23 (FBF23)
vitamin D

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8
Q

What does PTH cause stem cells to differentiate into? What about monocytes?

A

stem cells become preosteoblasts which become osteoblasts; monocytes become preosteoclasts which become osteoclasts

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9
Q

What does calcitriol (active VitD) do to Ca+ in the gut?

A

increases Ca+ absorption

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10
Q

What does calcitriol do to PTH release from parathyroid gland?

A

decreases it

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11
Q

What effect does FGF23 have on vitamin D?

A

decreases the formation of the active form

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12
Q

When rank ligand is released from osteoblasts, it can be taken away by (blank) to form an inactive RANKL/OPG complex

A

OPG

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13
Q

If rank ligand is allowed to bind to its receptors on osteoblast precursors, what does it form?

A

osteoclasts

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14
Q

an 84 amino acid peptide produced by the parathyroid gland

A

parathyroid hormone

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15
Q

Regulation of PTH is achieved in three ways. What are they?

A
  1. Ca+ sensitive protease cleaves PTH into fragments, so it limits PTH production
  2. Ca+ sensing receptor in parathyroid gland is stimulated by Ca+ to reduce PTH production and secretion
  3. The parathyroid gland contains the Vit D receptor and CYP27B1 to produce the active metabolite of Vit D to suppress PTH production
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16
Q

What does PTH do? It’s synthetic forms are Parathar or Teriparatide

A

Mobilizes calcium in bone
Decreases renal excretion of calcium
Stimulates Vit D synthesis
*Promotes phosphate excretion

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17
Q

Administration of PTH has limited use clinically. What is preferred?

A

Admin of Vit D3 and calcium (more direct effect)

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18
Q

Vitamin D biosynthesis: What takes 7-Dehydrocholesterol to Pre D3? What takes Pre D3 to D3? Where is D3 hydroxylated to 25(OH)D3? Where is 25(OH)D3 taken to its active form? What is the secondary product formed when the active form of Vit D is plentiful?

A

UV light; heat; liver; kidney; 24,25(OH)2D3 (secalciferol)

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19
Q

Why is secalciferol formed in addition to calcitriol?

A

When calcitriol is already plentiful, this is formed. When Ca++ and P are high

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20
Q

Calcitriol is derived from two sources

A

from the diet

generated in the skin as pro-vitD3 and then hydroxylation steps take place in liver and kidney

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21
Q

What part does PTH play in formation of active form of Vit D?

A

Increases it

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22
Q

T/F: Vit D and its metabolites circulate in the blood bound to Vit D binding protein and is rapidly cleared by the liver from the blood.

A

True

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23
Q

Vit D stimulates absorption of (blank) in the intestine and mobilization of (blank) from bone.

A

calcium and phosphate; calcium

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24
Q

Can be administered to treat osteomalacia and hypocalcemia associated with hypoparathyroidism.

A

Calcitriol

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25
Q

A single-chain protein with 251 amino acids that inhibits 1,25(OH)2D production and phosphate reabsorption in the kidney

A

fibroblast growth factor 23

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26
Q

What does fibroblast growth factor 23 do?

A

inhibits active Vit D production and phosphate reabsorption in the kidney

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27
Q

How is FGF23 produced?

A

produced by osteoblasts and osteocytes

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28
Q

How is FGF23 inactivated? What can mutations in this site lead to?

A

by cleavage at an RXXR site; Mutations in this site lead to excess FGF23, the underlying cause of autosomal dominant hypophosphatemic rickets

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29
Q

What stimulates FGF23 production directly? What inhibits FGF23 production indirectly?

A

1,25(OH)2D; DMP1

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30
Q

What can mutations in DMP1 lead to?

A

increased FGF23 and osteomalacia

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31
Q 
Effects of PTH on the following:
Intestine
Kidney
Bone
Net effect?
A

increased Ca and phosphate absorption (indirect)
decreased Ca excretion and increased P excretion
Ca and phosphate resorption from bone (high doses). Bone formation (low doses).
Net effect: serum Ca increase, serum phosphate decrease

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32
Q 
Effects of Vit D on the following: 
Intestine
Kidney
Bone
Net effect?
A

increased Ca and P absorption decreased Ca and P excretion
increased Ca and P resorption (may cause bone formation)
Net effect: serum Ca increase, serum phosphate increase

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33
Q 
Effects of FGF23 on the following:
Intestine
Kidney
Bone
Net effect?
A

Intestine: decreased Ca and P absorption because decreased calcitriol production
Kidney: increased phosphate secretion
Bone: decreased mineralization due to low phosphate and low calcitriol levels
Net effect: decreased serum phosphate

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34
Q

A number of hormones modulate PTH, FGF23, and VitD. The physiological impact of secondary regulators on bone mineral homeostasis are (blank), but can be exploited therapeutically

A

minor

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35
Q

Protein hormone (32 aa) produced by the thyroid gland. Overall effect is to lower plasma calcium. Used in the treatment of hypercalcemia associated with some neoplasms.

A

calcitonin

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36
Q

How is calcitonin regulated? Calcitonin inhibits (blank) and decreases reabsorption of both (blank) and (blank) in the proximal kidney tubules.

A

regulated by plasma calcium; osteoclasts; calcium and phosphate

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37
Q

Alter bone mineral homeostasis by antagonizing vitamin D-stimulated intestinal calcium transport, stimulating renal calcium excretion and blocking bone formation

A

glucocorticoids

38
Q

Glucocorticoids can be used pharmacologically to reverse (blank) associated with lymphomas and granulomatous diseases in which Vit D production is elevated

A

hypercalcemia

39
Q

Prolonged use of glucocorticoids can lead to (blank) in adults and (blank) in children

A

osteoporosis; stunted skeletal development

40
Q 
What can glucocorticoids do to the following:
bone quality
bone formation
bone resorption
bone mass
calcium balance
muscle weakness and myopathy
risk of fracture
A

decrease; decrease; increase; decrease; negative calcium balance; increase; increase

41
Q

What percentage of women’s bone mass is estrogen dependent?

A

10-20%

42
Q

Estrogens can prevent accelerated bone (blank) and transiently increase bone (blank) in postmenopausal women
Estrogens act to reduce the bone-resorbing actions of (blank)

A

loss; formation; PTH

43
Q

Estrogen increases blood levels of (blank), but has no direct effect its production. Increased (blank) as a result of estrogen treatment decreases serum calcium and phosphate

A

1,25[OH]2D (Calcitrol)

44
Q

Estrogen receptors are found in (blank) and estrogen has direct effects on bone (blank)

A

bone; remodeling

45
Q

What is the principle therapeutic action of estrogen?

A

to treat or prevent osteoporosis in post-menopausal women

*Long term use of estrogens may have adverse consequences

46
Q

Bone disease by characterized by a reduced quantity of bone

A

osteoporosis

47
Q

Bone disease characterized by a lack of mineralization

A

osteomalacia

48
Q

Bone disease characterized by the production of abnormal bone

A

Pagets disease

49
Q

Affects approximately 3% of the population over age 60
Disease of the bone that presents with bone pain, skeletal deformity, neurological complications or fractures
Incidence is highly variable: common in Central Europe, UK, Australia, New Zealand and USA. Rare in Africa, Middle East and Scandinavia
Pathology is excessive bone resorption and formation in 3 phases: osteolytic, osteoblastic and quiescent. All three phases may be present in the same patient at the same time

A

Pagets disease

50
Q

Caused by decreased mineralization of new bone matrix. In children, what does this lack of calcification result in?

A

osteomalacia; growth failure and deformity or Rickets

51
Q

How might an adult present with osteomalacia?

A

bone pain
proximal myopathy
fractures with minor trauma

52
Q

What is osteomalacia commonly caused by? What else can it be caused by?
What are some biomarkers?

A

Vit D deficiency;
insufficient exposure to sun, malnutrition
renal tubular acidosis; malnutrition during pregnancy; Malabsorption syndrome; Hypophosphatemia; Chronic renal failure; Tumor induced ostemalacia; Long term anti-convulsive therapy; Coelaic disease; Cadmium poisoning
biomarkers: low calcium, secondary elevation in PTH, low plasma Vit D

53
Q

Common disorder in post-menopausal women that may result in hip, forearm and spinal fractures
Caused by a thinning of the bone with aging
Increased morbidity and mortality

A

osteoporosis

54
Q

What is osteoporosis accelerated by?

A

premature or surgical loss of ovaries
drugs (corticosteroids)
lifestyle (alcohol, smoking)

55
Q 
What are these:
Increase in age
Female
Caucasian or Asian
Family history
Small stature
Low weight
Early menopause
Sedentary lifestyle
Low Ca+ intake
Alcoholic
Cigarette smoking
A

Risk factors for osteoporosis

56
Q

Bone formation increases from birth to (blank) years of age in men and women and then slowly declines

A

30

57
Q

T/F: With treatment after menopause, you can maintain bone mass. Without treatment, more bone can be lost.

A

True

58
Q

What happens to mortality risk following fractures?

A

It is elevated

59
Q

What test is used to determine bone density in women age 65 or older and patients aged 60 who are at an increased risk of osteoporosis?

A

Dual-energy X-ray (DEXA)

60
Q

In a DXA test, what T score indicates normal bone density? What T score indicates osteopenia (bone density below normal)? What T score indicates osteoporosis?

A

above -1
-1 to -2.5
less than -2.5

61
Q

Estrogen replacement therapy at the time of menopause inhibits the effect of (blank) on bone resorption and increases bone (blank)

A

osteoclasts; density

62
Q

What is the most widely prescribed medication for treatment of postmenopausal osteoporosis?

A

oral estrogens

63
Q

What is one downside to HRT?

A

may lead to increased cardiovascular events (esp for women with a history of disease)

64
Q

What HRT can be considered for patients that have not had a hyst?

A

progesterone

65
Q

In 2002 the Women’s Health Initiative showed that HRT causes an increase in strokes, heart attacks, breast cancer, blood clots, dementia, etc. So, current guidelines suggest that HRT be used to treat (blank) of menopause and for the (blank) period of time possible.

A

symptoms; shortest

66
Q

T/F: After a hysterectomy, estrogen-only hormone therapy does not increase a woman’s risk of breast cancer.

A

True!

67
Q

What are SERMs? What can they protect against?

A

SERMS are selective estrogen receptor modulators. They can act competitively on alpha estrogen receptors (ex: in the breast) to to prevent binding of estrogen. They can also act as agonists on beta estrogen receptors (ex: uterine tissue). They can protect against osteoporosis.

68
Q

What are two examples of SERMs that protect against osteoporosis?

A

tamoxifen

raloxifene

69
Q

This drug blocks the estrogen receptor in breast cancer cells whose growth is estrogen-dependent. It is now thought to be beneficial for the prevention of breast cancer in women at risk. It is often used in conjunction with surgical and or chemotherapeutic options.

A

Tamoxifen

70
Q

Tamoxifen can cause an increased risk in (blank) and has these side effects. It has some antiestrogenic side-effects but is not thought to alter lipid profiles or accelerate (blank)

A

endometrial cancer; hot flashes, nausea, vomiting; osteoporosis

71
Q

First approved as a treatment for osteoporosis. It has estrogenic activity but not on all sensitive tissues. It increases bone density and appears to decrease number of fractures. It can also decrease total cholesterol
patients taking the drug for the Tx of osteoporosis were followed for cancer and found to have a 50+% decrease in overall cancer incidence
Adverse effects include increased risk of thromboembolic events similar to estrogen. Some women report hot flashes and leg cramps

A

Raloxifene

72
Q

These are enzyme-resistant analogs of pyrophosphate (P-O-P structure replaced by P-C-P). They cause reduced turnover of bone by preventing the number and activity of osteoclasts. They take about 48 hrs to block bone resorption. They block the transformation of calcium phosphate into hydroxyapatite thus inhibitint the formation of these crystals in the bone.

A

bisphosphonates

73
Q

In general, what do bisphosphonates do?

A

decrease osteoclast activity

74
Q

bisphosphonates that increase bone density by 4-9% over the first 3 years of treatment and reduce vertebral fractures by 50%

A

etidronate
alendronate
risedronate

75
Q

This drug should not be given continuously because it may cause osteomalacia. Should be dosed over two weeks with periods off the drug

A

etidronate

76
Q

This drug 10mg/day can reduce the incidence of single vertebral fractures by 50% or 90% for multiple vertebral fractures

A

alendronate

77
Q

This drug 5mg/day can reduce the incidence of single vertebral fractures by 50% or 90% for multiple vertebral fractures

A

risedronate

78
Q

What should you avoid while taking bisphophates because they inhibit drug absorption? What are some adverse effects? What is the recommendation when taking them?

A

avoid milk products, food, or Ca+
may cause GI, gastric ulcers, erosive oseophagitis
take with water, avoid lying supine for 30 mins

79
Q

This drug inhibits the maturation of pre-osteoclasts into osteoclasts and therefore prevents bone resorption. It mimics the actions of osteoprogenin (OPG), an endogenous RANKL inhibitor that is decreased in patients with osteoporosis.

A

Denosumab

80
Q

Human monoclonal antibody against RANKL and is used for the treatment of osteoporosis, treatment of bone loss and bone metastasis, rhuematoid arthritis, multiple myeloma and giant cell tumor of the bone

A

Denosumab

81
Q

a synthetic C-19 steroid with weak hormonal properties. Short term studies have shown increases in bone mass in the spine and prevention of bone loss from the forearm in postmenopausal women

A

tiboline

82
Q

osteoporosis therapies

A

Ca supplements
Vit D analogs facilitate Ca2+ absorption from the gastrointestinal tract and may have an effect on bone formation and resorption
tibolone
teriparatide

83
Q

T/F: Calcium supplements have a small beneficial effect in preventing bone loss

A

True

84
Q

(PTH analog) used in cyclic doses has been shown to be effective in the treatment of osteoporosis

A

teriparatide

85
Q

Hypercalcemia is a life threatening condition. Fluid resuscitation is essential. What can be used to augment renal Ca++ excretion? What can rapidly reduce Ca++ but response is transient? What can help manage hypercalcemia?

A

loop diuretics; calcitonin; intravenous bisphosphates

86
Q

A calcium senor mimetic
Inhibits PTH secretion by the parathyroid gland
FDA approved for secondary hyperparathyroidism due to chronic kidney disease or hypercalcemia associated with parathyroid carcinoma

A

Cinacalcet

87
Q

T/F: Bone formation and resorption can be semi-quantified on bone biopsy or radiographic imaging

A

True

88
Q

T/F: Osteoporotic women have a higher incidence of fractures than incidence of heart attack, stroke, and breast cancer in women population combined.

A

True

89
Q

Precursors of osteoclasts express (blank), a member of the TNFR family. What is this activated by which is present on the surface of oesteoblasts and converts pre-osteoclasts to osteoclasts to resorb bone?

A

RANK; RANKL

So RANK, when bound to RANKL on the surface of osteoblasts, forms osteoclasts

90
Q

Adverse affects of Denosumab? Contraindications?

A

Adverse effects include increased urinary and respiratory tract infections, rashes, joint pain, eczema
Contraindications: Hypocalcemia

91
Q

Which drug causes the greatest % change in the lumbar spine in treatment of osteoporosis?

A

teriparatide

Block 4 Week 1 Meg (13 decks)

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