Pbl Exam 3 Case 3

Front 1

1. Why is the precise control of calcium concentration essential?

Back 1

Extracellular fluid concentration of calcium is regulated very precisely because calcium plays a key role in many physiologic processes, including contraction of skeletal, cardiac, and smooth muscles; blood clotting; and transmission of nerve impulses

Front 2

2. Hypercalcemia

Back 2

Causes progressive depression of the nervous system

Front 3

3. Hypocalcemia

Back 3

Causes progressive excitation of the nervous system and tetany

Front 4

4. About how much of the total body calcium is in the extracellular fluid?

In the cells?

In the bones?

Back 4

0.1% is in the extracellular fluid

1% in the cells

98.9% is stored in the bones; therefore, the bones can serve as large reservoirs, releasing calcium when extracellular fluid concentration decreases and storing excess calcium.

Front 5

5. About how much of the body's phosphate is stored in the extracellular fluid?

In the cells?

In the bones?

Back 5

< 1% is in the extracellular fluid

15% is in the cells

85% is stored in the bones.

Front 6

6. The calcium in the plasma is present in three forms.

What are they?

Back 6

1. About 41% of the calcium is combined w/the plasma proteins and in this form is nondiffusible through the capillary membrane.

2. About 9% of the calcium is diffusible through the capillary membrane but is combined w/anionic substances of the plasma and interstitial fluids in such a manner that is is not ionized.

3. The remaining 50% of the calcium in the plasma is both diffusible through the capillary membrane and ionized.

Front 7

7. Which form of calcium is important for most functions of calcium in the body?

Back 7

Ionic calcium

Front 8

8. Inorganic phosphate in the plasma is in what two forms?

Back 8

1. HPO4-
2. H2PO4-

Front 9

9. Changing levels of phosphates in the extracellular fluid vs. changing calcium levels

Back 9

Changing the level of phosphate in the extracellular fluid from far below normal to 2-3x normal does not cause major immediate effects on the body.

In contrast, even slight increases or decreases of calcium ion in the extracellular fluid can cause extreme immediate physiologic effects.

Front 10

10. Why does the nervous system become progressively more excitable in hypocalcemia?

Back 10

Hypocalcemia causes increased neuronal membrane permeability to sodium ions, allowing easy initiation of action potentials.

At plasma calcium ion concentrations about 50% 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.

It also occasionally causes seizures b/c of its action of increasing excitability in the brain.

Front 11

11. Carpopedal spasm

Back 11

Tetany in the hand, which usually occurs before tetany develops in most other parts of the body.

Front 12

12. At what calcium level does tetany occur?

Back 12

Tetany ordinarily occurs when the blood concentration of calcium falls from its normal level of 9.4 mg/dl to about 6 mg/dl, which is only 35% below the normal calcium concentration, and it is usually lethal at about 4 mg/dl.

Front 13

13. Why does the nervous system become depressed in hypercalcemia?

Back 13

When the level of calcium in the body fluids rises above normal, the nervous system becomes depressed and reflex activities of the CNS are sluggish.

Also, increased calcium ion concentration depresses the QT interval and causes lack of appetite and constipation, probably b/c of the depressed contractility of the muscle walls of the GI tract.

Front 14

14. At what calcium level do these depressive effects begin to appear?

Back 14

When the blood level of calcium rises above about 12 mg/dl, and they can become marked as the level rises above 15 mg/dl.

Around 17 mg/dl, calcium phosphate crystals are likely to precipitate throughout the body.

Front 15

15. Intestinal absorption and fecal excretion of calcium

Back 15

Normally, divalent cations such as calcium ions are poorly absorbed from the intestines.

However, vitamin D promotes calcium absorption by the intestines, and about 35% of the ingested calcium is usually absorbed; the remaining calcium in the intestine is excreted in the feces.

An additional amount of calcium enters the intestines via secreted GI juices and sloughed mucosal cells.

Thus, about 90% of the daily intake of Ca is excreted in the feces.

Front 16

16. Intestinal absorption and fecal excretion of phosphate

Back 16

Intestinal absorption of phosphate occurs very easily.

Except for the portion of phosphate that is excreted in the feces in combo with nonabsorbed Ca, almost all the dietary phosphate is absorbed into the blood from the gut and later excreted in the urine.

Front 17

17. Renal excretion of Ca

Back 17

Approx 10% of the ingested Ca is excreted in the urine.

About 41% of the plasma Ca is bound to plasma proteins and is therefore not filtered by the glomerular capillaries.

The rest is combined with anions such as phosphate (9%) or ionized (50%) and is filtered thru the glomeruli into the renal tubules.

Front 18

18. Where is the Ca reabsorbed in the kidneys?

Back 18

Normally, the renal tubules reabsorb 99% of the filtered Ca, and about 100 mg/day is excreted in the urine.

Approx 90% of the Ca in the glomerular filtrate is reabsorbed in the proximal tubules, loops of Henle, and early distal tubules.

Then in the late distal tubules and early collecting ducts, reabsorption of the remaining 10% is very selective, depending on the Ca ion concentration int he blood.

Front 19

19. Ca concentration changes and kidney reabsorption

What is the most important factor in controlling this reabsorption of calcium?

Back 19

When [Ca] is low, this reabsorption is great, so that almost no Ca is lost in the urine.

Conversely, even a minute increase in the blood Ca concnetration above normal increases calcium excretion markedly.

The most important factor in controlling this reabsorption of calcium in the distal portions of the nephron is PTH.

Front 20

20. How is renal phosphate excretion controlled?

Back 20

Via an overflow mechanism.

When the phosphate concentration in the plasma is below the critical value of about 1 mmol/L, all the phosphate in the glomerular filtrate is reabsorbed and no phosphate is lost in the urine.

Above this critical value, the rate of phosphate loss is directly proportional to the additional increase.

Thus, the kidneys regulate the phosphate concentration in the extracellular fluid by altering the rate of phosphate excretion in accordance with the plasma phosphate concentration and the rate of phosphate filtration by the kidneys.

*Also controlled by PTH

Front 21

21. Composition of bone in compact bone and newly formed bone

Back 21

Bone is composed of a tough organic matrix that is greatly strengthened by deposits of calcium salts.

The average compact bone contains by weight about 30% matrix and 70% salts.

Newly formed bone may have a considerably higher percentage of matrix in relation to salts.

Front 22

22. Organic matrix of bone

Back 22

90-95% collagen fibers, and the remainder is a homogeneous gelatinous medium called ground substance.

The collagen fibers extend primarily along the lines of tensional force and give bone its powerful tensile strength.

Front 23

23. Composition of ground substance

Back 23

Composed of extracellular fluid plus proteoglycans, especially chondroitin sulfate and hyaluronic acid.

Front 24

24. The crystalline salts deposited in the organic matrix of bone are composed principally of what two elements?

Back 24

1. Calcium
2. Phosphate

Front 25

25. What other ions are also present among the bone salts?

Back 25

1. Magnesium
2. Sodium
3. Potassium
4. Carbonate

Front 26

26. Conjugation of hydroxyapatite crystals

Back 26

The ions are believed to be conjugated to the hydroxapatite crystals rather than organized into distinct crystals of their own.

This ability of many types of ions to conjugated to bone crystals extends to many ions normally foreign to bone (i.e. heavy metals).

Deposition of radioactive substances in the bone can cause prolonged irradiation of the bone tissues, and if a sufficient amt is deposited, an osteogenic sarcoma eventually develops in most cases.

Front 27

27. What is the major crystalline salt in bone?

Back 27

Known as hydroxyapatite.

The relative ration of calcium to phosphorus can vary markedly under different nutritional conditions.

Front 28

28. Collagen fibers in bone

Back 28

Each collagen fiber of compact bone is composed of repeating periodic segments every 640 angstroms along its length; hydroxyapatite crystals lie adjacent to each segment of the fiber, bound tightly to it.

This intimate bonding prevents "shear" in the bone; that is, it prevents the crystals and collagen fibers from slipping out of place, which is essential in providing strength to the bone.

In addition, the segments of adjacent collagen fibers overlap one another, also causing hydroxyapatite crystals to be overlapped like bricks keyed to one another in a brick wall.

Front 29

29. What provides the tensile strength of bone?

Back 29

The collagen fibers of bone, like those of tendons, have great tensile strength

Front 30

30. What provides the compressional strength of bone?

Back 30

The calcium salts have great compressional strength.

Front 31

31. Does hydroxyapatite precipitate in extracellular fluid when calcium and phosphate ions are supersaturated?

Back 31

No, the inhibitors are present in almost all tissues of the body as well as in the plasma to prevent such precipitation; one such inhibitor is pyrophosphate.

Therefore, hydroxyapatite crystals fail to precipitate in normal tissues except in bone despite the state of supersaturation of the ions.

Front 32

32. Mechanism of bone calcification

Four steps...

Back 32

1. Secretions of collagen molecules and ground substance by osteoblasts.
2. The collagen monomers polymerize to form collagen fibers, forming an osteoid.
3. As the osteoid is formed, some of the osteoblasts become entrapped in the osteoid and become quiescent; thus forming osteocytes.
4. Within a few days calcium salts begin to precipitate on the surfaces of the collagen fibers, forming hydroxyapatite crystals.

Front 33

33. Are the initial calcium salts deposited on the fibers hydroxyapatite crystals?

Back 33

No, they are amorphous compounds (noncrystalline), a mixture of salts such as CaHPO4 x 2H2O, Ca3(PO4)2 x 3H2O.

Then, by a process of substitution and addition of atoms, or reabsorption and reprecipitation, these salts are converted into the hydroxyapatite crystals over a period of weeks or months.

Front 34

34. Are all of the amorphous compounds converted?

Back 34

No, a few percent remain permanently in the amorphous form.

This is important b/c these amorphous salts can be absorbed rapidly when there is need for extra calcium in the extracellular fluid.

Front 35

35. What causes the calcium salts to be deposited in the osteoids?

Back 35

Not fully understood.

The osteoids supposedly secrete a substance into the osteoid to neutralize the pyrophosphate that normally prevents hydroxyapatite crystallization.

Once the pyrophosphate has been neutralized, the natural affinity of the collagen fibers for calcium salts causes the precipitation.

Front 36

36. Precipitation of Ca in nonosseous tissues under abnormal conditions

Back 36

Alhtought calcium salts almost never precipitate in normal tissues besides bone, under abnormal conditions they do precipitate (i.e. arteriosclerosis, old blood clots)

Presumably, the inhibitor factors disappear from the tissues, thereby allowing precipitation.

Front 37

37. Equilibrium of calcium ions in bones and extracellular fluids

Back 37

The bone contains a type of exchangeable calcium that is always in equilibrium with the Ca ions in the extracellular fluids.

Thus, large increases or decreases in extracellular fluid concentrations can be minimized.

Front 38

38. Where is this exchangeable calcium found?

Back 38

A small portion is also found in all tissue cells, especially in highly permeable types of cells such as those of the liver and the GI tract.

However, most of the exchangeable Ca is in the bone.

Front 39

39. Importance of exchangeable calcium

Back 39

It provides a rapid buffering mechanism to keep the Ca ion concentration from rising to excessive levels or falling to very low levels.

Front 40

40. Deposition of bone by osteoblasts

Back 40

Bone is continually being deposited by osteoblasts, and it is continually being absorbed where osteoclasts are active.

Osteoblasts are found on the outer surfaces of the bones and in the bone cavities.

A small amt of osteoblastic activity occurs continually in all living bones, so that at least some new bone is being formed constantly.

Front 41

41. Function of the osteoclasts

Back 41

Absorption of bone.

Bone is also being continually absorbed din the presence of osteoclasts, which are large phagocytic multinucleated cells, derivatives of monocyte-like cells formed in the bone marrow.

The osteoclasts are normally active on less than 1% of the bone surfaces in an adult.

PTH controls the bone absorptive activity of osteoclasts.

Front 42

42. Where does bone absorption occur?

Back 42

Immediately adjacent to the osteoclasts.

Front 43

43. Mechanism of bone absorption

Four steps...

Back 43

1. The osteoclasts send out villus-like projections toward the bone.
2. The villi secrete proteolytic enzymes and several acids.
3. The enzymes digest or dissolve the organic matrix of the bone, and the acids cause solution of the bone salts.
4. The osteoclastic cells also imbibe by phagocytosis minute particles of bone matrix and crystals, eventually also dissoluting these and releasing the products into the blood.

Front 44

44. Bone deposition and absorption are...?

Back 44

Normally in equilibrium.

Normally, except in growing bones, the rates of bone deposition and absorption are equal to each other, so that the total mass of bone remains constant.

Osteoclasts eat the bone, forming a tunnel. Then, the tunnel is invaded by osteoblasts.

Bone deposition occurs, and continues for several months.

Front 45

45. How does bone deposition progress?

When does it stop?

Back 45

New bone is laid down in successive layers of concentric circles (lamellae) on the inner surfaces of the cavity until the tunnel is filled.

Deposition of new bone ceases when the bone begins to encroach on the blood vessels supplying the area.

Each new are of bone deposited in this way is called an osteon.

Front 46

46. What is the canal through which the blood vessels run called?

Back 46

The Haversian canal; it is all that remains of the original cavity.

Front 47

47. What are three advantages to having bone continually remodel itself?

Back 47

1. Bone ordinarily adjusts its strength in proportion to the degree of bone stress.
2. Even the shape of the bone can be rearranged for proper support of mechanical forces by deposition and absorption of bone in accordance with stress patterns.
3. B/c old bone becomes relatively brittle and weak, new organic matrix is needed as the old organic matrix degenerates.

Front 48

48. What controls the rate of bone deposition?

Back 48

Bone "stress"

Bone is deposited in proportion to the compressional load that the bone must carry.

Continual physical stress stimulates osteoblastic deposition and calcification of bone.

This stress also determines the shape of bones under certain circumstances.

Front 49

49. Repair of a fracture and osteoblasts

Back 49

Fracture of a bone maximally activates all the periosteal and intraosseous osteoblasts involved in the break.

Also, immense numbers of new osteoblasts are formed almost immeadiately from osteoprogenitor cells.

Front 50

50. What is a callus?

Back 50

Within a short time, a large bulge of osteoblastic tissue and new organic bone matrix, followed shortly by the deposition of Ca salts, develops between the two broken ends of the bone.

This is called a callus.

Front 51

51. Vitamin D

Back 51

Has a potent effect to increase Ca absorption from the intestinal tract; it also has important effects on both bone deposition and bone absorption.

Front 52

52. What must happen to vitamin D to cause these effects?

Back 52

Vitamin D must first be converted thru a succession of reactions in the liver and the kidneys to the final active product, 1,25-dihydroxycholecalciferol.

Front 53

53. What is cholecalciferol?

Where is it formed?

Back 53

AKA Vitamin D3

Several compounds derived from sterols belong to the vitamin D family, and they all perform the same functions.

Vitamin D3 is the most important of these and is formed in the skin as a result of irradiation of 7-dehdyrocholesterol by ultraviolet rays form the sun.

Front 54

54. What happens to the cholecalciferol after it is formed?

Back 54

It is then converted to 25-hydrocycholecalciferol, which happens in the liver.

This process is a limited one, b/c the 25-hydroxycholecalciferol has a feedback inhibitory effect on the conversion reactions.

Front 55

55. Why is the 25-hydroxycholecalciferol feedback inhibitory effect important?

Two reasons...

Back 55

1. The feedback mechanism precisely regulates the concentration of 25-hydroxycholecalciferol in the plasma, despite increased intake in Vitamin D.
2. The controlled conversion of vitamin D3 to 25-hydroxycholecalciferol conserves the vitamin D stored in the liver for future use. Once it is converted, it persists in the body for only a few weeks, whereas in the vitamin D form, it can be stored for months in the liver.

Front 56

56. What converts 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol?

Back 56

The conversion occurs in the proximal tubules of the kidneys. The final product is by far the most active form of vitamin D, b/c the previous products have less than 1/1000 of the vitamin D effect.

Therefore, in the absence of the kidneys, vitamin D loses almost all its effectiveness.

Front 57

57. What is required for the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol?

Back 57

PTH.

In the absence of PTH, almost none of the 1,25-dihydroxycholecalciferol is formed.

Front 58

58. What controls the formation of 1,25-dihydroxycholecalciferol?

Back 58

Calcium ion concentration controls the formation 1,25-dihydroxycholecalciferol.

The plasma concentration of 1,25-dihydroxycholecalciferol is inversely affected by the concentration of calcium in the plasma.

Front 59

59. What are the two reasons for the inverse relationship between Ca ion concentration and 1,25-dihydroxycholecalciferol?

Back 59

1. The calcium ion itself has a slight effect in preventing the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol.

2. Even more important, the rate of secretion of PTH is greatly suppressed when the plasma calcium ion concentration rises, and vice versa.

Front 60

60. Effect of vitamin D to promote intestinal calcium absorption

Back 60

1,25-dihydroxycholecalciferol itself functions as a type of "hormone" to promote intestinal absorption of calcium. It does this by increasing formation of a calcium-binding protein in the intestinal epithelial cells.

The rate of Ca absorption is directly proportional to the quantity of this Ca-binding protein.

Front 61

61. What are two other things formed by 1,25-dihydroxycholecalciferol that may play a role in promoting Ca absorption?

Back 61

1. A calcium-stimulated ATPase in the brush border of the epithelial cells

2. An alkaline phosphatase in the epithelial cells.

Front 62

62. Vitamin D and phosphate absorption by the intestines

Back 62

Vitamin D promotes phosphate absorption by the intestines.

Although phosphate is usually absorbed easily, phosphate flux thru the GI epithelium is enhanced by vitamin D.

It is believed that this results from a direct effect of 1,25-dihydroxycholecalciferol, but it is possible that it results secondarily from this hormone's action on calcium absorption, the calcium in turn acting as a transport mediator for the phosphate.

Front 63

63. Vitamin D and renal calcium and phosphate excretion

Back 63

Vitamin D decreases renal calcium and phosphate excretion.

Vit D also increases calcium and phosphate absorption by the epithelial cells of the renal tubules, thereby tending to decrease excretion of these substances in the urine.

Front 64

64. Effect of vitamin D and its relation to PTH activity when extreme quantities of vitamin D are administered

Back 64

Vitamin D plays important roles in both bone absorption and bone deposition.

The administration of extreme quantities of vitamin D causes absorption of bone.

Believed to result from the effect of 1,25-dihydroxycholecalciferol to increase Ca transport thru cellular membranes.

Front 65

65. Effect of vitamin D and its relation to PTH activity when smaller quantities of vitamin D are administered

Back 65

Vitamin D in smaller quantities promotes bone calcification.

One of the ways in which it does this is to increase Ca and phosphate absorption form the intestines.

However, even in the absence of such increase, it enhances the mineralization of bone.

Also probably results from the ability of 1,25-dihydroxycholecalciferol to cause transport of calcium ions thru cell membranes - but in this instance, perhaps in the opposite direction thru the osteoblastic or osteocytic cell membranes.

Front 66

66. Parathyroid hormone (PTH)

Back 66

PTH provides a powerful mechanism for controlling extracellular Ca and phosphate concentrations by regulating intestinal reabsorption, renal excretion, and exchange between the extracellular fluid and bone of these ions.

Front 67

67. Excess activity of the parathyroid gland causes...?

Back 67

Rapid absorption of Ca salts from the bones, with resultant hypercalcemia in the extracellular fluid.

Front 68

68. Hypofunction of the parathyroid gland causes...?

Back 68

Hypocalcemia, often with resultant tetany.

Front 69

69. Parathyroid glands

Back 69

Normally, there are four parathyroid glands in the human.

Removal of half the glands usually causes no major physiologic abnormalities.

However, removal of three of the four normal glands causes transient hypoparathryoidism.

Front 70

70. Composition of parathyroid glands

Back 70

Contains mainly chief cells, and a small to moderate number of oxyphil cells, but oxyphil cells are absent in many animals and in young humans.

The chief cells are believe to secrete most, if not all, of the PTH.

The funciton of the oxyphil cells is not certain, but they are believed to be modified or depleted chief cells that no longer secrete hormone.

Front 71

71. PTH synthesis

Back 71

First synthesized on the ribosomes in the form of a preprohormone, a polypeptide chain of 110 AAs.

This is cleaved first to a prohormone with 90 AAs and then to the hormone itself with 84 AAs by the endoplasmic reticulum and golgi apparatus.

Then, it is packaged in secretory granules in the cytoplasm of the cells.

Smaller compounds w/ as few as 34 AAs have been isolated that exhibit full PTH activity.

Front 72

72. Importance of smaller PTH fragments

Back 72

B/c the kidneys rapidly remove the whole 84 AA hormone within minutes but fail to remove many of the fragments for hours, a large share of the hormonal activity is caused by the fragments.

Front 73

73. PTH and calcium and phosphate concentrations

Back 73

Administration of PTH causes the calcium concentration to rise and phosphate concentration to fall.

Front 74

74. Why is the calcium concentration increased with PTH administration?

Two reasons...

Back 74

1. An effect of PTH to increase calcium and phosphate absorption from the bone

2. A rapid effect of PTH to decrease the excretion of Ca by the kidneys.

Front 75

75. What causes the decline in phosphate concentration when PTH is administered?

Back 75

Caused by a strong effect of PTH to increase renal phosphate excretion, an effect that is usually great enough to override increased phosphate absorption from the bone.

Front 76

76. What are two effects that PTH has on the bone?

Back 76

Has two effects on bone in causing
1. Absoprtion of calcium
2. Absorption of phosphate

Front 77

77. Two phases of calcium and phosphate absorption

Back 77

1. Rapid phase that begins in minutes and increases progressively for several hours; results from activation of osteocytes to promote calcium and phosphate absorption.

2. Much slower phase requiring several days or weeks to become fully developed; it results form proliferation of the osteoclasts, followed by greatly increased osteoclastic reabsorption of the bone itself, not merely absorption of the calcium phosphate salts from the bone.

Front 78

78. Where does PTH cause removal of bone salts?

Back 78

From two areas of the bone:
1. From the bone matrix in the vicinity of the osteocytes lying within the bone itself.
2. In the vicinity of the osteoblasts along the bone surface.

Front 79

79. Functions of osteoblasts or osteocytes

Back 79

Causes bone salt absorption

Front 80

80. Osteocytic membrane system

Back 80

Studies have shown that the osteoblasts and osteocytes form a system of interconnected cells that spreads all thru the bone and over all the bone surfaces except the small surface areas adjacent to the osteoclasts. Long, filmy processes extend from osteocyte to osteocyte throughout the bone structure, and these processes also connect w/the surface osteocytes and osteoblasts.

This system is called the osteocytic membrane system, and it is believed to provide a membrane that separates the bone itself from the extracellular fluid.

Front 81

81. Bone fluid

Back 81

Exists between the osteocytic membrane and the bone.

An osteocytic membrane pumps calcium ions form the bone fluid to the extracellular fluid, creating a calcium ion concentration in the bone fluid only 1/3 that in the extracellular fluid.

Front 82

82. Osteolysis

Back 82

When the osteocytic pump becomes excessively activated, the bone fluid calcium level falls even lower, and calcium phosphate salts are then absorbed from the bone.

It occurs without absorption of the bone's fibrous and gel matrix.

When the pump is inactivated, the bone fluid calcium concentration rises to a higher level and calcium phosphate salts are redeposited in the matrix.

Front 83

83. PTH and osteolysis

Back 83

The cell membranes of both the osteoblasts and the osteocytes have receptor proteins for binding PTH.

PTH can activate the calcium pump strongly, thereby causing rapid removal of Ca phosphate salts from those amorphous bone crystals that lie near the cells.

Front 84

84. How does PTH stimulate the Ca pump?

Back 84

It increases the Ca permeability of the bone fluid side of the osteocytic membrane, thus allowing calcium ions to diffuse into the membrane cells from the bone fluid.

Then the Ca pump on the other side of the cell membrane transfers the Ca ions the rest of the way into the extracellular fluid.

Front 85

85. PTH and activation of the osteoclasts

Back 85

Osteoclasts do not have membrane receptor proteins for PTH.

Instead, the activated osteoblasts and osteocytes send a secondary but unknown signal to the osteoclasts, causing them to become active.

Front 86

86. Activation of the osteoclastic system occurs in what two stages?

Back 86

1. Immediate activation of the osteoclasts that are already formed.
2. Formation of new osteoclasts.

Front 87

87. Prolonged excess PTH can cause what...?

Back 87

Can lead to weakened bones and secondary stimulation of the osteoblasts that attempt to correct the weakended state.

Still, even in the late stages, there is more bone absorption than bone deposition in the presence of continued excess PTH.

Front 88

88. PTH and phosphate excretion in the urine

Back 88

PTH causes rapid loss of phosphate in the urine owing to the effect of the hormone to diminish proximal tubular reabsorption of phosphate ions.

Front 89

89. PTH and calcium excretion in the urine

Back 89

PTH increases renal tubular reabsorption of calcium.

The increased calcium absorption occurs mainly in the late distal tubules, the collecting tubules, the early collecting ducts, and possible the ascending loop of Henle.

Front 90

90. cAMP and PTH

Back 90

A large share of the effect of PTH on its target organs is mediated by the cAMP second messenger mechanism.

The concentration of cAMP increases in osteocytes, osteoclasts, and other target cells.

This cAMP is responsible for such functions as osteoclastic secretion of enzymes and acids to cause bone reabsorption and formation of 1,25-dihydroxycholecalciferol in the kidneys.

Front 91

91. Conditions in which decreased calcium concentration causes parathyroid hypertrophy

Back 91

1. Rickets
2. Pregnancy
3. Lactation

Front 92

92. Conditions that increase the calcium ion concentration and cause reduced size of the parathyroid glands

Back 92

1. Excess quantities of calcium in the diet
2. Increased vitamin D in the diet
3. Bone absorption caused by factors other than PTH.

Front 93

93. Calcitonin

Back 93

A peptide hormone secreted by the thyroid gland.

Tends to decrease plasma calcium concentration and has effects opposite to those of PTH.

However, the quantitative role of calcitonin is far less than that of PTH in regulating Ca ion concentration.

Front 94

94. Synthesis and secretion of calcitonin

Back 94

Occur in the parafollicular cells, or C cells, lying in the intestinal fluid between the follicles of the thyroid gland.

These cells are remnants of the ultimobrachial glands of lower animals.

Front 95

95. Increased plasma calcium concentration and calcitonin secretion

Back 95

Increased plasma calcium concentration causes increased calcitonin secretion.

This provides a second hormonal feedback mechanism for controlling the plasma Ca ion concentration (but it is relatively weak).

Front 96

96. Calcitonin and plasma Ca concentration

Back 96

Calcitonin decreases plasma Ca concentration rapidly.

Front 97

97. What are the two ways by which calcitonin decreases Ca concentration in the plasma?

Back 97

1. Immediate effect is to decrease the absorptive activities of the osteoclasts and possibly the osteolytic effect of the osteocytic membrane throughout the bone, thus shifting the balance in favor of deposition of calcium in the exchangeable bone calcium salts.

2. More prolonged effect is to decrease the formation of new osteoclasts, which also leads to decreased osteoblastic activity.

Front 98

98. What are the two reasons for the weak effect of calcitonin on plasma calcium concentration in the adult?

Back 98

1. Initial reduction of Ca ion caused by calcitonin leads within hours to a powerful stimulation of PTH secretion which almost overrides the calcitonin effect.

2. In the adult, the daily rates of absorption and deposition of calcium are small -- the effect of calcitonin in children is much greater b/c bone remodeling occurs rapidly.

Front 99

99. What organelle also provides a calcium buffering function for the bones?

Back 99

The mitochondria - especially of the liver and intestine contains a reasonable amt of exchangeable Ca that provides an additional buffer system.

Front 100

100. In prolonged Ca excess or prolonged Ca deficiency, what mechanism seems solely important in maintaining a normal plasma Ca ion concentration?

Back 100

PTH

Front 101

101. Hypoparathyroidism

Back 101

The osteocytic reabsorption of exchangeable Ca decreases and the osteoclasts become almost totally inactive. As a result, calcium reabsorption from the bones is so depressed that the level of Ca in the body fluids decreases.

Yet, b/c Ca and phosphates are not being absorbed form the bone, the bone usually remains strong.

Front 102

102. What muscles are especially sensitive to tetanic spasm?

Back 102

Spasm of the laryngeal muscles; usually they are the cause of death in tetany unless appropriate treatment is applied.

Front 103

103. Treatment of hypoparathyroidism

Back 103

PTH is occasionally used.

However, in most patients, administration of large quantities of vitamin D and calcium keeps the calcium ion concentration in a normal range.

Sometimes, supplementation of 1,25-dihydroxycholecaliciferol is used but it is sometimes difficult to counteract if too much activity results.

Front 104

104. Primary hyperparathyroidism

What is the cause?

Back 104

An abnormality of the parathyroid glands causes inappropriate, excess PTH secretion.

Cause is a tumor of one of the parathyroid glands which occur more freq in women than in men or children due to pregnancy which causes hypertrophy of the glands.

Front 105

105. What does hyperparathyroidism cause?

Back 105

Causes extreme osteoclastic activity in the bones which elevates the calcium ion concentration in the extracellular fluid

Front 106

106. What is the main reason a person with hyperparathyroidism seeks medical attention?

Back 106

Bone fracture.

Radiographs of the bone feature extensive decalcification and large punched-out cystic areas of the bone that are filled with osteoclasts in the form of so called giant cell osteoclast tumors.

Front 107

107. Osteitis fibrosa cystica

Back 107

The cystic bone disease of hyperparathyroidism is called Osteitis fibrosa cystica

Front 108

108. Alkaline phosphatase

Back 108

When osteoblasts become active, they secrete large quantities of alkaline phosphatase.

One of the more important diagnostic findings in hyperparathyroidism is an elevated ALKPHOS.

Front 109

109. Parathyroid poisoning and metastatic calcification

Back 109

When extreme quantities of PTH are secreted, the calcium and phosphate in the body fluids become greatly supersaturated so that calcium phosphate crystals deposit in the alveoli of the lung, the tubules of the kidneys, the thyroid gland, the acid producing area of the stomach mucosa, and the wall of the arteries thoughout the body.

Front 110

110. Formation of kidney stones in hyperparathyroidism

Back 110

Most patients with mild hyperparathyroidism have an extreme tendency to form kidney stones.

Excess Ca and phosphate absorbed from the intestines causes increase in the concentrations of these substances in the urine.

*Making the urine more acidic helps prevent formation of renal calculi.

Front 111

111. What is the main cause of secondary hyperparathyroidism?

Back 111

High levels of PTH occur as a compensation for hypocalcemia rather than as a primary abnormality of the parathyroid glands.

Can be caused by vitamin D deficiency or chronic renal disease.

Front 112

112. Rickets

Back 112

Occurs mainly in children caused by a lack of vitamin D.

Children who remain indoors throughout winter are usually asymptomatic until the spring months b/c vitamin D formed during the preceding summer is stored in the liver and available for use during the early winter months.

Causes weakened bones, and tetany in later stages.

Front 113

113. Treatment of rickets

Back 113

Depends on supply adequate calcium and phosphate in the diet and on administering large amts of vitamin D.

Front 114

114. Osteomalacia

Back 114

Adult rickets.

Serious deficiencies of both vitamin D and calcium occasionally result from steatorrhea in which vitamin D and calcium tend to pass into the feces.

Almost never proceeds to the stage of tetany but often is a cause of sever bone disability.

Front 115

115. Osteomalacia and rickets caused by renal disease

Back 115

Renal rickets is a type of osteomalacia that results from prolonged kidney damage.

Front 116

116. Congenital hypophosphatemia

Back 116

Another type of renal disease that leads to rickets and osteomalacia.

Results from congenitally reduced reabsorption of phosphates by the renal tubules.

This type of rickets must be treated with phosphate compounds instead of calcium and vitamin D, and it is called vitamin D-resistant rickets.

Front 117

117. What are the 6 main causes of osteoporosis?

Back 117

1. Lack of physical stress on the bones
2. Malnutrition
3. Lack of vitamin C
4. Postmenopausal lack of estrogen
5. Old age
6. Cushing's syndrome

Front 118

118. Dysotoses

Back 118

Developmental anomalies resulting from localized problems in the migration of mesenchymal cells and their formation of condensations are known as dysotoses.

Front 119

119. Dysplasias

Back 119

Mutations in the regulators of skeletal organogenesis, such as cellular signaling mechanisms, and matrix components, affect cartilage and bone tissues globally, and these disorders are known as dysplasias.

Front 120

120. What are the seven classifications of genetic disorders?

Back 120

1. Defects in nuclear proteins and transcription factors
2. Defects in hormones and signal transduction mechanism
3. Defects in extracellular structural proteins
4. Defects in folding and degradation of molecules
5. Defects in oncogenes and tumor suppressor genes
6. Defects in metabolic pathways
7. Defects in RNA and DNA processing and metabolism

Front 121

121. Developmental and acquired abnormalities in bone cells, matrix, and structure

Back 121

Developmental anomalies are freq genetically based and manifest during early stages of bone formation; acquired diseases are usually detected in adulthood.

Front 122

122. Synpolydactyly

Back 122

Caused by a mutation in the homeobox HOXD-13 transcription factor.

The mutation manifests as an extra digit between the third and fourth digits with some fusion of the fingers.

Front 123

123. Achondroplasia

Back 123

The most common form of dwarfism.

Anatomically, the growth plates are shortened and disordered, resulting in abnormally short extremity bones.

B/c appositional growth is not affected, bone are of normal width and the skull appears comparatively enlarged.

Front 124

124. What causes achondroplasia?

Back 124

It results from a defect in paracrine cell signaling the growth plate cartilage, namely a gnetic derangement in the gene that codes for FGF receptor 3 located on chromosome 4. Some cases are familial, but most are acquired mutations.

Front 125

125. Heterozygous achondroplasia

Back 125

Heterozygotes ahve normal longevity with easily recognizable disease b/c head and body are too large for the markedly shortened extremities.

Metal, sexual and reproductive development are normal.

Front 126

126. Thanatophoric dwarfism

Back 126

The most common form of lethal dwarfism.

Causes by a different mutation in FGF receptor 3, and the dysfunctional growth plates produce micromelic shortening of the limbs, relative macrocephaly, and a constricted thoracic cage that causes death soon after birth.

Front 127

127. Osteogenesis imperfecta

Back 127

AKA brittle bone disease

Refers to a group of closely related genetic disorders caused by qualitatively or quantitatively abnormal type I collagen synthesis.

The underlying genetic defect is mutation in the genes that code for the alpha 1 and alpha 2 chains fo the collagen molecule.

Consequently, the bones are prone to fracture.

Front 128

128. What are the different types of osteogenesis imperfecta?

Back 128

Four major subsets are classified.

They range from one variant (type II) that is uniformly fatal in the perinatal period (from multiple bone fractures) to other variants marked by increased predisposition to fracture but compatible with survival.

Front 129

129. Type I variant of osteogenesis imperfecta

Back 129

More often due to an acquired rather than an inherited mutation, permits a normal life span but with an increased number of fractures during childhood that decrease in frequency after puberty.

Front 130

130. Type II variant of osteogenesis imperfecta

Back 130

It is uniformly fatal in utero or during the perinatal period.

It is characterized by extraordinary bone fragility with multiple fractures occurring when the fetus is still within the womb.

Front 131

131. Morphological changes in osteogenesis imperfecta

Back 131

The basic change is osteopenia (too little bone), with marked thinning of the cortices and rarefaction (decrease in density) of the trabeculae.

Front 132

132. What types of collagens are important structural components of hyaline cartilage?

Back 132

Types 2, 10, and 11 collagens.

Front 133

133. Mucopolysaccharidoses

Back 133

A group of lysosomal storage diseases caused by deficiencies in enzymes (mainly acid hydrolases) that degrade the various mucopolysaccharides.

Chondrocytes play a role in mucopolysaccharide metabolism; consequently, in these disorder there are abnormalities in hyaline cartilage including growth plates, costal cartilages, and articular surfaces.

Patients are freq of short stature and have malformed bones as well as other cartilage abnormalities.

Front 134

134. Osteopetrosis

Back 134

Refers to a group of rare genetic diseases characterized by reduces osteoclastic activity resulting in diffuse skeletal sclerosis w/loss of the medullary cavity (with impaired hematopoiesis).

Despite too much bone, it is brittle and fractures like chalk.

Front 135

135. What is osteopetrosis associated with?

Back 135

Severe forms are evident at birth and are associated with anemia, neutropenia, infections, and eventually death.

Patients with benign forms of the disease are predisposed to fractures.

Front 136

136. What is the underlying genetic defect in osteopetrosis?

Specific gene mutations?

Back 136

Aberrant osteoclast function resulting in reduced bone resorption and an increase in bone mass

The nature of the genetic defect has been identified for some forms.; these including mutations in the genes that code for carbonic anhydrase II and CIC-7 chloride channel.

Front 137

137. Morphological changes associated with osteopetrosis

Back 137

Grossly the bones lack a medullary canal and the ends of long bones are bulbous (Erlenmeyer flask deformity) and misshapen.

The neural foramina are small and compress exiting nerves.

Bone that forms is not remodeled and tends to be woven in architecture. In the end, these intrinsic abnormalities cause the bone to be brittle.

Front 138

138. Clinical features of infantile malignant osteopetrosis

Back 138

Autosomal recessive and usually becomes evident in utero or soon after birth. Fracture, anemia, and hydrocephaly are often seen, resulting in postpartum mortality.

Patients who survive into their infancy have cranial nerve problems, and repeated, often fatal, infections b/c of decreased hematopoiesis resulting from the reduced marrow space.

Patients develop extramedullary hematopoiesis, which causes hepatosplenomegaly.

Front 139

139. Clinical features of autosomal dominant benign form of osteopetrosis

Back 139

May not be detected until adolescence or adulthood, when it is discovered on X-rays performed b/c of repeated fractures.

These patients may also have milder cranial nerve deficits and anemia.

Front 140

140. Treatment for osteopetrosis

Back 140

B/c osteoclasts are derived from marrow monocyte precursors, bone marrow transplants provide affected patients with progenitor cells that can produce normal functioning osteoclasts.

Front 141

141. Osteoporosis

Back 141

Refers to a reduction in bone mass owing to small but incremental losses occurring with the constant turnover of bone.

Seen most often in the elderly of both sexes but it is more pronounced in post-menopausal women.

Can occur as a primary disorder of obscure origin or as a secondary complication of a large variety of diseases.

Front 142

142. When does osteoporosis become clinically significant?

Back 142

When it induces vertebral instability with back pain and increases the risk for fractures of hips, wrists, and vertebral bodies.

Front 143

143. What are the two most common forms of osteoporosis?

Back 143

1. Senile osteoporosis
2. Post-menopausal osteoporosis

Front 144

144. Pathogenesis of senile osteoporosis

Back 144

Genetic factors determine the peak bone mass achieved in young adulthood. Thereafter, aging-related slowing of osteoblast formation and function, decreased biologic activity of matrix bound growth factors and diminished physical activity results in senile osteoporosis.

Categorized as a low turnover variant

Front 145

145. Pathogenesis of post-menopausal osteoporosis

Back 145

There is also an increase in osteoclastic activity induced by decreased serum estrogen levels.

The diminished estrogen levels result in increased secretion of IL-1, IL-6, and TNF by blood monocytes.

These cytokines are potent stimulators of osteoclast recruitment and activity by increasing the levels of RANK and RANKL and reducing osteoprotegrin (OPG).

Compensatory osteoblastic activity occurs, but it does not keep pace w/the bone loss.

Front 146

146. RANK

Back 146

Receptor activator for nuclear factor kB

RANK is a member of the TNF family of receptors expressed mainly on cells of macrophage/monocytic lineage such as preosteoclasts.

When this receptors binds its specific ligand (RANKL) through cell-cell contact, osteoclastogenesis is initiated.

Front 147

147. RANKL

Back 147

Receptor activator for nuclear factor kB ligand.

Produced by an expressed on the cell membranes of osteoblasts and marrow stromal cells; its major role in bone metabolism is stimulation of osteoclast formation, fusion, differentiation, activation, and survival.

Front 148

148. Osteoprotegrin (OPG)

Back 148

The actions of RANKL can be blocked by another member of the TNF family of receptors, osteoprotegrin (OPG).

OPG is a soluble protein produced by a number of tissues, including bone, hematopoietic marrow cells, and immune cells.

OPG inhibits osteoclastogenesis by acting as a decoy receptor that binds to RANKL, thus preventing the interaction of RANK with RANKL.

Therefore, interplay between bone cells and these molecules permits osteoblasts and stromal cells to control osteoclast development.

Front 149

149. Morphology of osteoporosis

Back 149

In postemenopausal and senile forms, the entire skeleton is involved, but patients may have loaclized disease due to immobilization or extremity paralysis

Cortex and trabeculae are thinned, and haversian systems are widened

Also, residual bone is of normal composition.

Front 150

150. Clinical features of osteoporosis

Back 150

Causes pain due to microfractures. It results in loos in height and stability of the vertebral column, and particularly predisposes to fractures of femoral necks, wrists, and vertebrae.

Complication of overt fractures, such as PE and pneumonia, are frequent and result in 40,000-50,000 deaths/year.

Front 151

151. Why is osteoporosis difficult to diagnose?

Back 151

1. It remains asymptomatic until skeletal fragility is well advanced
2. There is no easy way to determine the severity of the bone loss (radiographs are unreliable w/less than 40% bone loss); most reliable are absorptiometry and quantitative computed tomography.

Front 152

152. Prevention and treatment of osteoporosis

Back 152

Includes exercise, appropriate calcium and vitamin D intake, and phamacologic agents, including estrogen replacement agents, bisphosphonates, and recombinant PTH.

The latter increases skeletal mass by stimulating the formation of bone in amounts greater than that which is resorbed.

Front 153

153. Paget disease

Back 153

AKA osteitis deformans

It is a skeletal disease that can be characterized as a collage of matrix madness.

Is monostotic in about 15% of cases and polyostotic in the remainder with the extent of the disease varying from site to site.

Front 154

154. What are the three sequential stages in Paget disease?

Back 154

1. Initial osteolytic stage
2. Mixed osteolytic-osteoblastic stage
3. Evolving ultimately into a burnt-out, quiescent osteosclerotic stage

Front 155

155. Pathogenesis of Paget disease

Back 155

The presumed cause is a paramyxovirus infection of osteoclasts.

Viral particles have been identified in osteoclasts but the virus itself has not been isolated.

Also, predisposition of Paget disease has been linked to chromosome 18q.

Front 156

156. Morphology of osteolytic phase in Paget disease

Back 156

Marked by resorption by numerous, overly large osteoclasts (some containing >100 nuclei)

Front 157

157. Morphology of mixed phase in Paget disease

Back 157

Has new disordered, predominantly woven bone formation. The new bone is poorly mineralized, and is therefore soft and porous, lacking structural stability, and thus, the bone is vulnerable to fracture or defromation under stress.

In this stage, units of lamellar bone are deposited in a tile-like or mosaic pattern, which is a pathognomonic feature of Paget disease.

Also, adjacent marrow is fibrotic.

Front 158

158. Morphology of burnt-out phase in Paget disease

Back 158

Marked predominantly by bone sclerosis composed of a mosaic pattern of lamellar bone with coarsely thickened trabeculae and cortices

Front 159

159. Clinical features of Paget disease

Back 159

Patheitns may demonstarte fractures, nerve compression, OA, and skeletal deformities (e.g. tibial bowing, skull enlargement)

Any bone can be involved, and coarsening of the facial bones may produce leontiasis ossea (lion-like facies).

Less commonly, the vascularity of polyostotic lesions can cause high output heart failure. Occasionally, in about 1% of patients, secondary sarcoma develops.

Front 160

160. Rickets and osteomalacia

Back 160

Rickets in growing children and osteomalacia in adults are caused by defects in matrix mineralization and frequently result from either vitamin D deficiency or phosphate depletion.

Front 161

161. Morphology of Rickets and osteomalacia

Back 161

The fundamental defect is failure to mineralize bone; this causes excess unmineralized matrix and abnormally wide osteoid seams.

Front 162

162. Clinical features of Rickets and osteomalacia

Back 162

In the growing child, the skeleton is weak with bowing of legs and deformities of ribs, skull, and other bones.

In adults, after bone growth has ceased- it results in no skeletal deformities, but does cause osteopenic osteomalacia.

Front 163

163. What does hyperparathyroidism lead to?

Back 163

1. Increased levels of PTH
2. Increased osteoclastic activity occurs, with resorption of bone and peritrabecular fibrosis (osteitis fibrosa)
3. Unabated bone resorption predisposes to microfractures, fibrosis, and secondary hemorrhage with formation of cysts within the marrow cavity
4. Bone loss is particularly evident by x-ray as subperiosteal bone resorption along the radial aspect of the middle phalanges of the index and middle fingers and distal clavicles and loss of the lamina dura about the tooth sockets
5. So called "brown tumors" (resembling reparative giant cell granulomas) also occur within the bones

Front 164

164. Renal osteodystrophy

Back 164

Refers to a complex set of bone changes appearing in most patients with chronic renal failure.

Increased osteoclastic activity, delayed matrix mineralization (osteomalacia), osteosclerosis, growth retardation, and osteoporosis.

With protracted skeletal disease, metastatic calcifications can also develop in the skin, eyes, arterial walls, and joints.

Other factors that contribute to the bone changes include metabolic acidosis and iron and aluminum deposition in bone (derived from dialysate, and interfering with matrix mineralization)

Front 165

165. Speed of healing and perfection in fractures

Back 165

Depends on the type of fracture and whether the break has occurred in normal bone or in previously diseased bone (i.e. pathologic fracture)

Front 166

166. What types of fractures heal most rapidly?

Back 166

Well aligned, incomplete (greenstick), and closed (intact skin) fractures heal most rapidly, with potentially complete reconstitution of the preexisting architecture.

Front 167

167. What types of fractures heal the slowest?

Back 167

Comminuted (splintered bone) and compound (open skin wound) fractures heal much more slowly, with poorer end results.

Front 168

168. Morphology of bone fracture healing

Back 168

Fracture healing is regulated by cytokines and growth factors, and is a continuous process proceeding through three distinct stages

Front 169

169. What are the three stages of bone fracture healing?

Back 169

1. Organization of the hematoma at the fracture site, leading to a soft, organizing, procallus.

2. Conversion of the procallus to a fibrocartilaginous callus composed of reactive mesenchymal cells.

3. Replacement of the latter by an osseous callus, which is eventually remodeled along line so weight bearing to complete the repair.

Front 170

170. Perfection of bone fracture repair

Back 170

If the fracture has been well aligned and the original weight bearing strains are restored, virtually perfect repair is accomplished.

Imperfect results are seen when there is malalignment, comminution, inadequate immobilization of fracture site, infection, and superimposed systemic abnormality (e.g. atherosclerosis, avitaminosis, dietary deficiency, osteoporosis)

Front 171

171. Osteonecrosis (avascular necrosis)

Back 171

Infarction of the bone and marrow is relatively common and can occur in the medullary cavity of the metaphysis or diaphysis and the subchondral region of the epiphysis.

Front 172

172. What are the mechanisms that lead to local ischemia in avascular necrosis?

Back 172

1. Vascular interruption (fracture)
2. Thrombosis and embolism (caisson disease)
3. Vessel injury (vasculitis, radiation therapy)
4. Vascular compression (possibly steroid-induced necrosis)
5. Venous hypertension

Front 173

173. What is the most common mechanism of avascular necrosis?

Back 173

Steroid-induced necrosis is most common.

Front 174

174. Morphology of avascular necrosis

Back 174

A local geographic area of pale yellow infarction is seen in the marrow (the cortex is usually not affected b/c of its collateral blood flow).

The necrotic region is marked by death of osteocytes, empty lacunae, and necrotic fat cells. Creeping substitution with living tissue occurs from the margin of the infarct.

In subchondral infarcts, the articular cartilage may collapse into the necrotic bone.

Front 175

175. Clinical features of avascular necrosis

Back 175

Patients may be asymptomatic, but subchondral lesions often cause joint pain and predispose to subsequent osteoarthritis.

Front 176

176. Pyogenic osteomyelitis

Back 176

Results from bacterial seeding of bone by:
1. Hematogenous spread
2. Extension from a contiguous infection
3. Open fracture or surgical procedure

Front 177

177. What is the most often implicated bacteria in pyogenic osteomyelitis?

Back 177

Staphylococcus aureus (often penicillin resistant)

For obscure reasons, patients with sickle cell anemia are prone to Salmonella infectiosn.

Extension of infection or traumatic inoculation is freq associated with mixed infections, including anerobes.

Front 178

178. Morphology of pyogenic osteomyelitis

Back 178

Basically, the suppurative inoculation is frequently associated with ischemic necrosis, fibrosis, and bony repair.

Front 179

179. Specific alterations of bone in pyogenic osteomyelitis

Back 179

1. Necrosis of a bone segment may produce a sequestrum
2. Subperiosteal new bone produces and involucrum that encloses and envelops the inflammatory focus.
3. Chronic cases may lead to bone deformities and sinus tracts. Small walled-off intracortical abscesses are known as a Brodie abscess.

Front 180

180. Clinical features of pyogenic osteomyelitis

Back 180

An acute febrile illness with local pain, tenderness and heat. Subtle lesions, however, may present as unexplained fever in infants or localized pain without fever in adults.

During the first 10 days, x-ray changes may be minimal, but radionuclide studies often show localized uptake of tracers.

Complications include fracture, amyloidosis, bacteremia with endocarditis, and development of squamous cell carcinoma in sinus tract.

Front 181

181. Prevalence of tuberculous osteomyelitis

Back 181

This has experienced a resurgence in developed countries attributed to the influx of immigrants from developing countries and the greater numbers o fo immunosuppressed patients.

It remains common in developing countries where pulmonary and GI tuberculosis are still prevalent.

Front 182

182. Tuberculous osteomyelitis

Back 182

It arises as a blood borne infection, which is much more destructive and resistance to control than suppurative diseases.

In the spine, it is called Pott disease

It produces typical granulomatous reaction with caseous necrosis.

Front 183

183. What are the two forms of skeletal syphilis?

Back 183

Although rare in the US, syphilitic bone disease can occur in either congenital or acquired forms.

Front 184

184. Congenital skeletal syphilis

Back 184

Appears at birth and is marked by periostitis. On x-ray, a crew-haircut like appearance of new bone formation of cortex is produced.

Saber shin results when the tibia is involved.

Front 185

185. Acquired skeletal syphilis

Back 185

Appears in the tertiary stage of the disease.

It may be manifested as periostitis but more often by bone gummas.

Front 186

186. What are the classes of antiresporptive agents?

Back 186

1. Hormone replacement therapy
2. Selective estrogen receptor modulators
3. Bisphosphonates
4. Calcitonin

Front 187

187. What are the classes of bone anabolic agents?

Back 187

1. Fluoride
2. PTH

Front 188

187. Estrogen HRT and osteoporosis

Back 188

Estrogen acts to reduce bone resorption by suppressing the transcription of genes coding for cytokines, such as IL-6, that induce osteoclast proliferation, differentiation, and activation.

Estrogen also promotes the apoptosis of osteoclasts while inhibiting the apoptosis of osteoblasts and osteocytes.

Estrogen does not increase bone formation, but it does maintain bone mass or slow bone loss thru its antiresorptive properties.

Front 189

188. How is estrogen administered?

Back 189

Administered cyclically with a progestational agent to reduce the risk of endometrial cancer.

Front 190

189. What are some risks with estrogen HRT?

Back 190

1. Vaginal bleeding
2. Breast tenderness
3. Increased risk of thromboembolism
4. Increased long term risk of breast CA
5. Cardiovascular disease
6. Stroke

Front 191

190. Contraindications of estrogen HRT

Back 191

1. Breast CA
2. Endometrial CA
3. Cerebral vascular or CAD
4. Benign or malignant liver tumors
5. Severe hypertension
6. Pregnancy
7. Thrombotic dieases

Front 192

191. Selective estrogen receptor modulators (SERM)

Back 192

Used in the prevention and treatment of postmenopausal osteoporosis.

SERMs are a group of compounds that bind to the estrogen receptor and have tissue-selective effects on the target organs of estrogen.

Depending on the tissue, a SERM is capable of acting as an estrogen agonist or an estrogen antagonist.

Front 193

192. What are the two actions of SERM complexes?

Back 193

1. Bind selectively to tissue specific hormone response elements

and/or

2. Recruit tissue selective transcriptional co-repressors and co-activators.

Front 194

193. Unique goal of SERMs

Back 194

The goal of SERM development is to retain the beneficial effects of estrogen in one or more tissues, while eliminating the undesirable effects of estrogen in other tissues.

Front 195

194. Raloxifene

Back 195

A SERM that is approved for the prevention and treatment of osteoporosis.

It increases women's bone density without increasing the risk of endometrial cancer. (Estrogen agonist in bone; estrogen antagonist in endometrium and breast)

Also, it may reduce the risk of estrogen receptor positive breat CA.

Also reduces serum total and LDL cholesterol.

Front 196

195. Adverse effects of Raloxifene

Back 196

Retinal vascular occlusion, venous thromboembolism, hot flashes, leg cramps.

Front 197

196. Raloxifene contraindications

Back 197

1. Pregnancy
2. History or presence of venous thromboembolism

Front 198

197. Bisphosphates; how do they work?

Back 198

Most widely used class of antiresorptive drugs, are analogues of pyrophosphate.

They work by:
1. Inhibiting the osteoclastic proton pump necessary for dissolution of hydroxyapatite (decreases solubility of hydroxyapatite)
2. Decreasing osteoclastic formation/activation
3. Increasing osteoclastic apoptosis via inhibition of the mevalonate pathway

Front 199

198. What are the names of the bisphosphonates?

Five of them...

Back 199

1. Alendronate
2. Ibandronate
3. Pamidronate
4. Risedronate
5. Zoledronic acid

Front 200

199. What are the bisphosphonates used for?

Back 200

1. Osteoporosis prevention and treatment
2. Paget's disease
3. Hypercalcemia of malignancy (pamidronate and zoledronic acid)
4. Also shown to decrease the number of bone and visceral metastases in patients with breast CA

Front 201

200. Adverse effects of bisphosphonates

Back 201

Esophageal pain and erosion, esophagitis and ulcers, jaw osteonecrosis, acid reflux, headache

Front 202

201. Contraindications of bisphosphonates

Back 202

1. Esophageal erosions
2. Delayed gastric emptying
3. Hypocalcemia
4. Inability to sit up for 30 min after taking orally
5. Renal impairment

Front 203

202. Pharmacokinetics of bisphosphonates

Back 203

Zaledronate and pamidronate are administered via IV. All other are orally active.

Food significantly interferes with absorption. Should be administered with 6-8 oz of water at least one hour before eating breakfast.

Ibandronate (Boniva) can be given as a monthly formation.

Front 204

203. What are the potency levels of the bisphosphonates?

Back 204

Antiresporptive activity:

Pamidronate: 100
Alendronate: 100-1000
Risedronate: 1000-10,000

Front 205

204. Calcitonin

Back 205

Salmon calcitonin is administered intranasally, is effectve and well tolerated in postmenopausal women at risk of developing osteoporosis.

The drug reduces bone resorption and improves bone architecture, relieves pain, and increases function.

Unfortunately, tolerance occurs with continuous use.

Front 206

205. How does calcitonin work?

Back 206

It binds to and activates a G protein-coupled receptor on osteoclasts, thereby decreasing the resorptive activity of these cells.

B/c of this action, exogenous calcitonin can be used to treat conditions characterized by high osteoclastic activity.

Salmon calcitonin has a higher affinity for the human calcitonin receptor and a longer half-life than human calcitonin.

Front 207

206. Therapeutic uses of calcitonin

Back 207

1. Osteoporosis
2. Hyercalcemia
3. Paget's disease

Front 208

207. Adverse effects of calcitonin

Back 208

Facial flushing, nausea, diarrhea, anorexia

Front 209

208. Contraindications of calcitonin

Back 209

Hypersensitivity to salmon calcitonin

Front 210

209. Misc facts about calcitonin

Back 210

1. Weak analgesic activity
2. Nasal-spray formation used most widely
3. Plicamycin may enhance hypocalcemic effect.

Front 211

210. When are anti-resorptive agents NOT optimal therapies?

Back 211

If patients have already lost a large amount of bone mass (BMD > than 3.0 standard deviations below normal) or if they have already experienced one or more osteoporotic fragility fractures.

Front 212

211. Fluoride

Back 212

Fluoride is a mitogen (agent that triggers mitosis) for osteoblasts.

Clinical studies have shown that fluoride, at concentrations higher than those used to fluoridate public water systems, increases trabecular bone mass.

Use of fluoride, however, leads to the conversion of hydroxyapatite to fluoroapatitie, which is denser but more brittle.

This agent is still begin investigated.

Front 213

212. Once daily PTH(1-34)

Back 213

Increases bone remodeling, but with more new bone formed than old bone resorbed.

The increase in bone formation occurs b/c PTH acutely promotes osteoblast differentiation and stimulates osteoblast activity.

Front 214

213. Why is the PTH administered once daily?

Back 214

Once-daily subcutaneous administration of PTH favors bone anabolism, while high continuous exposure to PTH favors bone catabolism.

Front 215

214. Therapeutic uses of PTH(1-34)

Back 215

Severe osteoporosis

Front 216

215. Adverse effects of PTH(1-34)

Back 216

Hypotension, syncope, arthralgias

Front 217

216. Contraindications of PTH(1-34)

Back 217

Hypersensitivity to PTH

Front 218

217. Generic name for PTH(1-34)

Back 218

Teriparatide

Front 219

218. What are the three phamacologic approaches to treating secondary hyperparathyroidism?

Back 219

1. Oral phosphate binders
2. Vitamin D and analogues
3. Calcimimetics

Front 220

219. Oral phosphate binders - why are they used?

Back 220

In patients with chronic kidney disease, the increased plasma phosphate can complex w/circulating Ca.

The resulting decrease in plasma Ca can lead to hyperparathyroidism.

Goal here is to decrease phosphates to stop hyperparathyroidism.

Front 221

220. What are the three oral phosphate binders?

Back 221

1. Aluminum hydroxide
2. Calcium carbonate/acetate
3. Sevelamer

Front 222

221. Aluminum hydroxide

What is it used to treat?

Back 222

Aluminum precipitates with phosphate in the GI tract, leading to the formation of nonabsorbable complexes.

Used to treat chronic kidney disease, however, it is rarely used due to its adverse effect profile.

Front 223

222. Adverse effects of aluminum hydroxide

Back 223

Confusion with chronic administration (neurotoxicity), anemia, osteomalacia, and constipation

Front 224

223. Contraindications of aluminum hydroxide

Back 224

Hypersensitivity to aluminum hydroxide

Front 225

224. Calcium carbonate/acetate

What are they used to treat?

Back 225

Often used to lower plasma phosphate; these agents bind dietary phosphate and thereby inhibit its absorption.

Used to treat:
1. Chronic kidney disease
2. Osteoporosis
3. Hypocalcemia
4. Antacid

Front 226

225. Adverse effect of calcium carbonate/acetate

Back 226

Milk-alkali syndrome and constipation

Front 227

226. Contraindications of calcium carbonate/acetate

Back 227

1. Hypercalcemia
2. Vitamin D toxicity

Front 228

227. Pharmacokinetics of calcium carbonate/acetate

Back 228

Calcium carbonate requires acidic environment for effective action

Calcium acetate is effective in acidic or alkaline environment.

Front 229

228. Sevelamer

How does it work and what is it used to treat?

Back 229

A nonabsorbable cationic ion-exchange resin that binds intestinal phosphate, thereby decreasing the absorption of dietary phosphate.

It also binds bile acids, leading to interruption of the enterohepatic circulation and to decreased cholesterol absorption.

Used to treat chronic kidney disease

Front 230

229. Adverse effects of sevelamer

Back 230

1. Thrombosis
2. Hypertension
3. Constipation

Front 231

230. Contraindications of sevelamer

Back 231

1. Hypophosphatemia
2. Bowel obstruction

Front 232

231. Vitamin D and analogues

Back 232

B/c impaired synthesis of 1α-vitamin D derivatives is one of the main disturbances leading to secondary hyperparathyroidism in chronic kidney disease, vitamin D is a logical replacement therapy.

All of these agents bypass the need for 1α-hydroxylation in the kidney; and are therefor useful in the treatment of bone diseases that complicate renal failure.

Front 233

232. How do vitamin D and analogues work?

Back 233

Active vitamin D increases dietary absorption of calcium, and the resulting increase in plasma Ca suppresses the secretion of preformed PTH by chief cells of the parathyroid gland.

In addition, these agents bind to and activate vitamin D receptors on the chief cells, and thereby suppress PTH gene transcription.

Front 234

233. Calcitriol

Back 234

This is the dihydroxylated form of vitamin D3. It is available in oral and IV forms.

It should not be administered to patients with chronic kidney disease until hyperphosphatemia has been controlled b/c the addition of calcitriol can caused increase plasma levels of both calcium and phosphate.

Front 235

234. Paricalcitol

Back 235

This is a synthetic analogue of vitamin D that may lower plasma PTH levels without significantly raising plasma calcium levels.

Front 236

235. Doxecalciferol

Back 236

This is the 1α-hydroxylated form of vitamin D2; it is 25-hydroxylated to the full active 1,25-dihydroxy form in the liver.

Front 237

236. Therapeutic uses of vitamin D and analogues

Back 237

1. Chronic kidney disease (secondary hyperparathyroidism)
2. Hypoparathyroidism
3. Rickets
4. Osteomalacia
5. Osteoporosis

Front 238

237. Adverse effects of vitamin D and analogues

Back 238

Hypercalcemia, renal calculi, hypophosphatemia, edema (paricalcitol)

Front 239

238. Contraindications of vitamin D and analogues

Back 239

1. Hypercalcemia
2. Vitamin D toxicity

Front 240

239. Misc facts for vitamin D and analogues

Back 240

1. Calcitriol is the preferred agent if rapid therapeutic action is desired.
2. Calcitriol also used in treatment of vitamin D dependent Rickets
3. Paricalcitol may cause less hypercalcemia than calcitriol.

Front 241

240. Calcimimetics

Back 241

Vitamin D and analogues can lead to unwanted hypercalcemia and hyperphosphatemia.

The calcimimetics, agents that modulate the activity of the Ca-sensing receptor on the chief cells - may be effective treatments for hyperparathyroidism that do not cause these unwanted effects.

Front 242

241. Cinacalcet

Back 242

A calcimimetic that binds to the transmembrane region of the Ca-sensing receptor, thereby modulates receptor activity by increasing its sensitivity to Ca.

B/c the cinacalcet-bound receptor is activated at lower Ca concentrations, PTH synthesis and secretion are also suppressed at lower Ca concentrations.

Front 243

242. What is cinalcalcet used to treat?

Back 243

1. Chronic kidney disease
2. Parathyroid carcinoma.
3. Primary hyperparathyroidism (off-label use)

Front 244

243. Adverse effects of cinacalcet

Back 244

Hypocalcemia, hypertension, dizziness

Front 245

244. Contraindications of cinacalcet

Back 245

Hypersensitivity to cinacalcet

Front 246

245. Oral calcium (Calcium gluconate/carbonate)

What is it used to treat?

Back 246

Has both therapeutic and prophylactic utility.

Used to treat:
1. Vitamin D-dependent rickets
2. Hypoparathyroidism
3. Hypocalcemia
4. Osteoporosis.

Front 247

246. Adverse effects of calcium gluconate/carbonate

Back 247

Headache, GI disturbance, renal calculi

Front 248

246. Contraindications for calcium gluconate/carbonate

Back 248

Hypersensitivity to calcium gluconate/carbonate

Front 249

247. Pharmacokinetics of calcium gluconate/carbonate

Back 249

When administered via IV, calcium gluconate causes less venous irritation

Front 250

248. Denosumab

Back 250

A fully humanized antibody against RANK ligand that may inhibit bone resorption.

In clinical trials.

Front 251

249. Strontium ranelate

Back 251

Approved in Europe for the treatment of osteoporosis.

Mechanism of action has not been identified, but it has been reported to inhibit bone resorption and stimulate bone formation.

Front 252

249. Why is the maintenance of normal calcium homeostasis critical to survival?

Three reasons...

Back 252

1. Serum calcium concentrations regulate the degree of membrane excitability in muscle and nervous tissue

2. Terrestrial life requires the existence of a skeleton, and Ca is the major structural cation in the skeleton.

3. Intracellular calcium has a major intracellular signaling role, and control of intracellular calcium is essential to the survival of all cells.

Front 253

250. What is the normal serum total Ca concentration?

What about in other areas of the body?

Back 253

Approximately 9.5 mg/dL

Approx 4.5 mg/dL is bound to serum proteins

Approx 0.5 mg/dL circulates as insoluble complexes such as calcium sulfate, phosphate, and citrate.

The remaining approx 4.5 mg/dL circulates as free or unbound or ionized calcium.

Front 254

251. What are the three critical regulatory fluxes that maintain normal serum calcium concentration?

Back 254

1. Intestine
2. Kidney
3. Skeleton

Front 255

252. Where does intestinal Ca absorption take place?

Back 255

Occurs in the duodenum and proximal jejunum.

Front 256

253. Pathologic increases in serum Ca can be caused by...?

Back 256

1. Increases in circulating vitamin D as in sarcoidosis
2. Excessive calcium intake (the milk-alkali syndrome)

Front 257

254. Pathologic decreases in serum Ca can be caused by...?

Back 257

Decline in vitamin D (chronic renal failure and hypoparathyroidism)

Front 258

255. What is the most important moment-to-moment regulator of the serum calcium concentration?

Back 258

The kidney.

Front 259

256. Where is calcium reabsorbed in the kidney?

Which parts are subject to PTH influence?

Back 259

90% is reabsorbed proximally, in the proximal convoluted tubule, the pars recta, and the tick ascending limb of Henle's loop. This 90% is not subject to PTH influence.

The remaining 10% that arrives at the distal tubule on a daily basis is subject to regulation, with PTH stimulating renal Ca reabsorption.

Front 260

257. A healthy person is in _____ calcium balance with respect to the outside world.

Back 260

A healthy person is in zero calcium balance with respect to the outside world.

Front 261

258. What are the two types of bone in the adult skeleton?

Back 261

1. Cortical (or lamellar)
2. Trabecular

Front 262

259. Cortical bone

Back 262

Predominates in the skull and the shafts of the long bones.

Front 263

260. Trabecular bone

Back 263

Predominates at other sites, such as the distal radius, the vertebral bodies, and the trochanters of the hip.

Most osteoporotic fractures occur at sites in which trabecular bone predominates.

Front 264

261. What are the components of the osteoid?

Back 264

1. Collagen
2. Osteocalcin
3. Osteopontin
4. Osteonectin
5. TGF-β
6. Insulin-like growth factor-1
7. Proteoglycans

Front 265

262. Howship's lacunae

Back 265

Osteoclasts move along the surface of trabecular bone plates and drill tunnels in cortical bone, periodically releasing the digested contents w/in their sealed zones into the bone marrow space and thereby creating resorption lacunae, or Howship's lacunae.

Front 266

263. PTH actions on kidneys

Back 266

(Direct)

1. Stimulate 1,25(OH)2D production
2. Stimulate cAMP production
3. Stimulate Ca reabsorption
4. Block phosphate reabsorption

Front 267

264. PTH actions on bone

Back 267

(Direct)

1. Activate osteoclastic resorption (acute)
2. Activate osteoblastic bone formation (subacute, chronic)

Front 268

265. PTH action on intestines

Back 268

(Indirect)


Activates Ca transport (indirectly via 1,25(OH)2D)

Front 269

266. Vitamin D

Back 269

Really two different compounds:
1. Ergocalciferol (vitamin D2)
2. Cholecalciferol (vitamin D3)

Both substances are actually inactive precursors, one derived principally from skin exposed to sunlight (D3) and the other derived from plant sterols (D2).

Front 270

267. Hepatic osteodystrophy

Back 270

Severe liver disease such as cirrhosis prevents one of the essential steps of vitamin D formation and leads to vitamin D-deficient syndromes called hepatic osteodystrophy.

Front 271

268. Hypoparathyroidism vs. hyperparathyroidism

Back 271

The hypocalcemia of hypoparathyroidism is a result of inadequate intestinal calcium absorption.

Conversely,hyperparathyroidism is associated with hypercalciuria and nephrolithiasis, both of which are direct results of increses in circualting 1,25(OH)2D.

Front 272

269. Subacute or chronic suppression of PTH results in...?

Back 272

Reduction in circulating 1,25(OH)2D; this action, in turn, leads to a reduction in the efficiency of Ca absorption from the intestine and a reduction of Ca entry into the extracellular fluid and hence a reduction of urinary calcium excretion.

Also a chronic decrement in PTH leads to a chronic decline in osteoblastic activity such that no osteoid is formed, and the ability to deposit Ca into the skeletal sink is lost.

Front 273

270. A chronic low calcium intake would lead to a chronic elevation in PTH and this results in...?

Back 273

An increase in 1,25(OH)2D.

This increase, in turn, leads to an increase in the efficiency of Ca absorption from the intestine to compensate for the reduction in dietary intake.

Also, a chronic elevation in PTH will lead to an increase in osteoblast activity and osteoid synthesis, with resultant increases in skeletal Ca deposition.

Net skeletal Ca losses will be negligible or normal.

Front 274

271. Phosphate

Back 274

A negatively charged, trivalent phosphate ion (PO4)

It regulates or participates in the regulation of an enormous number of biologic processes.

The actions of phosphate are fundamental to life itself.

Front 275

272. What are the 6 actions of phosphate?

Back 275

1. Integral component of the DNA double helix
2. Shuttling oxygen from Hgb to cells and vice versa using 2,3-diphosphoglycerate
3. Intracellular signaling via kinases that attach phosphate groups to other molecules
4. Facilitate critical intracellular messenger systems such as cAMP and inositol phosphate
5. Maintain basic intracellular redox status via the NADP-NADPH system
6. Serve as the gateway to the glucose metabolic pathway thru glucose-6-phosphate

Front 276

273. Is phosphorus primarily an intra- or extracellular ion?

Back 276

Primarily an intracellular ion.

Extracellular concentrations are less important b/c the ECF functions mainly as a transport conduit thru which phosphorus must travel from the skeleton or intestine to reach the cell interior.

Front 277

274. Phosphate and bone integrity

Back 277

Anion pairs of phosphate with calcium in the hydroxyapatite crystal lattice provides structural integrity to the skeleton.

Front 278

275. What are the two corollaries of broad and critical intracellular roles for phosphate?

Back 278

1. Clinically significant intracellular phosphate deficiency may exist w/o marked hypophoshatemia

2. Importantly, severe, life-threatening phosphate deficiency is often unrecognized b/c its manifestations are so completely nonspecific yet common in intensive care unit settings (reduced levels of consciousness, hypotension, respirator dependence, and weakness).

Front 279

276. What are two reasons why serum phosphorus is maintained in a broad range?

Back 279

1. Extracellular phosphate concentrations are not critically important.

2. B/c phosphate is so abundant inside plant and animal cells, phosphate is abundant in almost any diet such that evolutionary pressure has not been intense to develop a systemic regulatory mechanism for phosphate.

Front 280

277. Where does intestinal absorption of phosphate occur?

Back 280

Also in the duodenum and jejunum.

Front 281

278. What are some conditions of dietary phosphorus deficiency?

Back 281

1. Chronic alcoholism
2. Intensive care units w/o adequate oral or parenteral alimentation
3. Intestinal malabsorption
4. Phosphate-biding antacid use

Front 282

279. When are skeletal calcium fluxes important?

Back 282

Skeletal destruction in multiple myeloma or sever immobilization syndromes leads not only to hypercalcemia, but also to hyperphosphatemia, which, with the concomitant hypercalcemia, leads to nephrocalcinosis and renal failure.

Conversely, osteoblastic metastases in prostate CA and breast CA and the hungry bone syndrome following parathyroidectomy all lead to clinically significant hypophosphatemia.

Front 283

280. When are intracellular-extracellular phosphate fluxes important?

Back 283

In the setting of metabolic acidosis, phosphate leaves the intracellular compartment and may lead to hyperphosphatemia, whereas, under conditions of alkalosis, serum phosphate concentrations decline, and hypophoshatemia develops as phosphate enters the intracellular compartment.

Other settings include crush injury (rhabdomyolysis) and the tumor lysis syndrome, in both of which large intracellular loads of phosphate are delivered into the ECF and result in hypocalcemia, seizures, nephocalcinosis and renal failure.

Lastly, glucose shifts phosphate into cells as G6P and overzealous caloric restitution in the undernourished patient can result in severe hypophosphatemia and sudden death.

Front 284

281. What is the most important mechanism for maintaining a normal serum phosphorus conenctration?

Back 284

Renal phsophorus handling.

As w/Ca, phosphate is filtered by the glomerulus.

Tubular reabsorption of filtered phosphate (TRP) occurs at a rate such that approximately 90% of phosphate is reabsorbed.

Front 285

282. Fe(pi)

Back 285

The remaining 10% represents the fractional excretion of phosphorus

Fe(pi) = (urine PI / urine creatinine) x (serum creatinine / serum phosphorus)

Front 286

283. Calculating the TRP

Back 286

TRP = 1 - Fe(pi)

Front 287

284. Ellsworth-Howard test

Back 287

The initial bioassay for PTH action in humans which asses the responsiveness of the TRP to infusion of bovine parathyroid gland extract.

Front 288

285. TmP

Back 288

Tubular maximum for phosphorus-glomerular filtration rate

TmP values below 1.0 mmol or 2.5 mg/dL are abnormal and indicate phosphaturia.

Front 289

286. Excessive PTH vs. low PTH and TmP

Back 289

Excessive PTH lowers the TmP

Low PTH values allow the TmP to rise to supranormal levels.

Front 290

287. What other factors regulate the level of the TmP?

Back 290

A phosphaturic hormone that has been called phosphatonin.

Despite decades of research, not much has been found about this compound.

Other factors:
PHEX enzyme failure
FGF-23
MEPE
sFRP4

Front 291

288. PHEX enzyme

Back 291

X-linked hypophosphatemic rickets, AKA vitamin D-resistant rickets, causative inactivating mutations have been identified in the PHEX enzyme.

Current models suggest that mutant PHEX fails to inactivate normal amounts of phosphatonin, and this failure leads to phosphaturia and hyophosphatemia.

Front 292

298. FGF-23

Back 292

In autosomal-dominant hypophosphatemic rickets and oncogenic osteomalacia, overproduction of fibroblast growth factor-23 has been demonstrated, and many clinicians believe that FGF-23 is the long-sought phosphatonin.

Front 293

299. MEPE or sFRP4

Back 293

Other investigators believe that these may serve as phosphatonins as well.

Front 294

300. Magnesium

Back 294

A divalent cation, has closer parallels with phosphorus homeostasis.

Both magnesium and phosphate are principally intracellular, w/concentrations inside the cell that far exceed those outside the cell.

Front 295

301. Role of magnesium

Back 295

Governs key intracellular processes.

1. DNA replication and transcription
2. Translation of RNA
3. Use of ATP as an energy source
4. Regulated peptide hormone secretion

Front 296

302. Regulation of magnesium concentration

Back 296

Little evolutionary pressure to develop a complex regulatory network exists due to its abundance inside all kinds of cells.

Front 297

303. Life threatening Mg deficiency

Back 297

Life threatening Mg deficiency is often undetected b/c its symptoms are frustratingly nonspecific: weakness, respirator dependence, diffuse neurologic syndromes including seizures, and cardiovascular collapse.

Front 298

304. When can a Mg deficiency occur?

Back 298

1. Alcoholism
2. Intensive care unit settings in which adequate nutrition often is not provided
3. Intestinal malabsorption

Front 299

305. Magnesuria is caused by...?

Back 299

1. Saline infusions
2. Diuretic use
3. EtOH use
4. Secondary hyperaldosteronism states such as cirrhosis and ascites.

Front 300

306. FeMg

Back 300

This is the fractional excretion of Mg and can be calculated to determine whether the kidney is appropriately conserving Mg instates of hypmagnesemia or whether renal Mg wasting is the cause of hypomagnesemia.

Normal FeMg is 2-4%; hypomagnesemic individuals should display values below 1-2%.

Front 301

307. Bone strength reflects primarily the integration of what two main features?

Back 301

1. Bone density
-reflects the peak adult bone mass and the amount of bone lost in adulthood

2. Bone quality
-determined by bone architecture, bone geometry, bone turnover, mineralization, and damage accumulation (i.e. microfractures)

Front 302

308. Major risk factors for osteoporosis

Back 302

1. Personal history of fracture in adulthood
2. Fracture history in a first degree relative
3. Low body weight (< 127 lbs)
4. Current smoking
5. Use of oral corticosteroids for longer than 3 months

Front 303

309. Other risk factors for osteoporosis

Back 303

1. Impaired vision
2. Early estrogen deficiency (younger than 45 y/o)
3. Dementia
4. Poor health and/or frailty
5. Recent falls
6. Low calcium intake
7. Low physical activity
8. EtOH consumption

Front 304

310. What are the risk factors for hip fracture in postmenopausal women over 65?

Back 304

1. Age
2. History of maternal hip fracture
3. Weight
4. Height
5. Poor health
6. Previous hyperthyroidism
7. Current use of long acting benzos
8. Poor depth perception
9. Tachycardia
10. Previous fracture
11. Low bone mineral density

Front 305

311. Bone mass and ethnicity

Back 305

Men have a higher one mass than women.

African Americans and Hispanics have a higher bone mass than whites.

Front 306

312. Genetic factors and bone mass

Back 306

Multiple gene, including vitamin D-receptor alleles, estrogen receptor genes, and the high bone mass gene, are thought to be associated w/bone mass, but studies are ongoing.

Front 307

313. What are the medications that commonly cause bone loss?

Back 307

1. Excess thyroid hormone
2. Glucocorticoids
3. Anticonvulsants
4. Heparin
5. Gonadotropin-releasing hormone agonists

Front 308

314. Clinical features of osteoporosis

Back 308

Considered a silent disease until fractures occurs.

Whereas 90% of hip fractures occur following a fall, 2/3 of vertebral fractures are silent and occur w/minimal stress such as lifting, sneezing, and bending.

An acute vertebral fracture may result in significant back pain, which decreases gradually over several weeks w/analgesics and physical therapy.

Patients w/significant vertebral osteoporosis may have height loss, kyphosis, and severe cervical lordosis.

Front 309

315. Dx of osteoporosis

Back 309

Made following an acute clinical fracture or w/bone mineral densitometry assessment.

Radiographs can reveal a vertebral compression fracture, however, radiologic evidence of low bone mass may not be present until 30% of bone mass has been lost.

Thus, radiographs are a poor indicator of osteoporosis, and the Dx is often made based on bone mineral densitometry.

Front 310

316. Bone mineral density and osteoporosis

Back 310

Osteoporosis is defined as a bone mineral density less than or equal to 2.5 standard deviations below young adult peak bone mass

Front 311

317. Bone mineral density and osteopenia

Back 311

Defined as a bone mass measurement below 1.0 and 2.5 standard deviations below adult peak bone mass.

Front 312

318. What is the normal bone mineral density with regards to standard deviations?

Back 312

Above 1.0 standard deviations below adult peak bone mass.

Front 313

319. What is the gold standard for assessing bone mineral density?

Back 313

Dual energy X-ray absorptiometry

Has excellent precision and accuracy.

Measurements are made of the hip and spine and approx 30% of the time, discordance is found between these measurements.

Therefore, classification is based on the lowest value (total spine, total hip, femoral neck, or trochanter)

Front 314

320. Other ways of measuring bone mineral density

Back 314

Quantitative computed tomography (qCT)

However, few normative data have been found for hip qCT, vertebral precision is inferior to that of DXA, and radiation doses are significantly higher than those of DXA.

Finally, single-photon absorptiometry of the forearm and peripheral measures, such as finger DXA and heel ultrasound, have also been used to assess bone mass.

Front 315

321. Skeletal sites and device used for measuring bone mineral density

Back 315

The avg woman would be diagnosed with osteoporosis at age 60 when assessing the lateral spine but not until she is over 100 if heel ultrasound is used.

Although all of these measurements have an accuracy of 1-3%, precision is best w/forearm or spine DXA (approx 1%).

Front 316

322. Bone mineral density screen recommendations

Back 316

Every 2 years, depending on the site to be assessed and the type of therapy prescribed.

For example, trabecular bone, which is more metabolically active than cortical bone, is more likely to show improvements w/stronger acting antiresportive agents.

Changes in bone mass w/potent antiresportive therapy are more prominent in the spine compared w/other areas.

Seeing no changes in forearm bone mineral density over time is common, despite good precision.

Also, the heel has a high percentage of trabecular bone, however; precision is poor and monitoring should not be done at this site.

Front 317

323. Bone mass measurement recommendations for different patients

Back 317

In general, DXA examines the spine and hip.

However, in patients w/hyperparathyroidism, in which cortical bone loss is often seen, forearm DXA should also be assessed.

Older patients w/osteoporosis often have falsely elevated bone mineral density measurements at the spine as a result of atypical calcification.

Front 318

324. Why are lateral bone mineral density measurements difficult to perform?

Back 318

Overlap of the ribs on L2 and overlap of the pelvic brim on L4.

Classification should only be made if two or more vertebrae are available for analysis b/c of the high error rate when only one vertebra is assessed.

Front 319

325. Treatment recommendations and T-scores

Back 319

Recommended for all patients w/a bone density at least 2.5 standard devs below peak bone mass.

Only preventative measures are recommended for patients w/scores at -1.5 or above.

For patients w/scores between -1.5 and -2.5, treatment depends on the number and severity of risk factors.

Front 320

326. Vertebroplasty and kyphoplasty

Back 320

Involves injection of cement into a compressed vertebra to prevent the vertebral body from further collapse.

Alternatively, kyphoplasty introduces a balloon into the vertebral body to expand it, followed by cement placement inside the balloon.

This approach not only expands the vertebral body, but also increases some of the height.

Currently, these procedures are only recommended for patients w/significant pain from vertebral fractures and are not routinely performed in asymptomatic patients w/vertebral osteoporosis.

Front 321

327. Geriatric psychiatry

Back 321

Concerned w/preventing diagnosing, and treating psychological disorders in older adults.

It is also concerned with promoting longevity; persons w/a healthy mental adaptation to life are likely to live longer than those stressed w/emotional problems.

Front 322

328. Differences between younger persons and older adults in psychiatry

Back 322

Mental disorders in the elderly often differ in clinical manifestations, pathogenesis, and pathophysiology from disorders of younger adults and do not always match the categories int he DSM.

Diagnosing and treating older adults can present more difficulties than treating younger persons b/c older persons may have coexisting chronic medical diseases and disabilities, may take many medications, and may show cognitive impairments.

Front 323

329. Prevalence of mental disorders in elderly persons

Back 323

Vary widely, but a conservatively estimated 25% have significant psychiatric symptoms. The number of mentally ill elderly person is expected to rise to 20 million by the middle of the century.

Front 324

330. Predisposing psychosocial risk factors for mental disorders in the elderly

Back 324

Many lasses, such as those of social roles, autonomy and independence, family and friends, health, and finances.

Front 325

331. Cognitive disorders that are common in the elderly

Back 325

Ranges from minor age related memory impairments (benign senescent forgetfulness)

to

Full blown dementias, such as Alzheimer's disease

Front 326

332. Dementia

Back 326

The second most common cause of disability in people over 65 years of age, after arthritis.

It is a generally progressive and irreversible impairment of the intellect, the prevalence of which increases with age.

Front 327

333. How does dementia differ from mental retardation?

Back 327

In contrast to mental retardation, the intellectual impairment of dementia develops over time- that is, previously achieved mental functions are lost gradually.

Front 328

334. What are the characteristics of dementia?

Back 328

The characteristic changes of dementia involve cognition, memory, language, and visuospatial functions, but behavioral disturbances are common as well and include agitation, restlessness, wandering, rage, violence, shouting, social and sexual disinhibition, impulsiveness, sleep disturbances, and delusions.

Delusions and hallucinations occur during the course of the dementias in nearly 75 percent of patients.

Front 329

335. Cortical vs. subcortical dementias

Back 329

Depending on the site of the cerebral lesion, dementias are classified as cortical and subcortical.

A subcortical dementia occurs in Huntington's disease, Parkinson's disease, normal pressure hydrocephalus, vascular dementia, and Wilson's disease.

The subcortical dementias are associated with movement disorders, gait apraxia, psychomotor retardation, apathy, and akinetic mutism, which can be confused with catatonia.

In clinical practice, the two types of dementias overlap and, in most cases, an accurate diagnosis can be made only by autopsy

Front 330

336. Signs and symptoms of depressive disorders

Back 330

The common signs and symptoms of depressive disorders include reduced energy and concentration, sleep problems (especially early morning awakening and multiple awakenings), decreased appetite, weight loss, and somatic complaints.

Front 331

337. How do depressive disorder in the elderly differ from younger individuals?

Back 331

The presenting symptoms may be different in older depressed patients from those seen in younger adults because of an increased emphasis on somatic complaints in older persons.

Older persons are particularly vulnerable to major depressive episodes with melancholic features, characterized by depression, hypochondriasis, low self-esteem, feelings of worthlessness, and self-accusatory trends (especially about sex and sinfulness) with paranoid and suicidal ideation.

Front 332

338. Dementia syndrome of depression (pseudodementia)

Back 332

Can be confused easily with true dementia. In true dementia, intellectual performance usually is global, and impairment is consistently poor; in pseudodementia, deficits in attention and concentration are variable.

Compared with patients who have true dementia, patients with pseudodementia are less likely to have language impairment and to confabulate; when uncertain, they are more likely to say "I don't know"; and their memory difficulties are more limited to free recall than to recognition on cued recall tests

Front 333

339. Paraphrenia

Back 333

A late-onset delusional disorder called paraphrenia is characterized by persecutory delusions. It develops over several years and is not associated with dementia. Some workers believe that the disorder is a variant of schizophrenia that first becomes manifest after age 60.

Patients with a family history of schizophrenia show an increased rate of paraphrenia.

Front 334

340. Hypochondriasis

Back 334

Hypochondriasis is common in persons over 60 years of age, although the peak incidence is in those 40 to 50 years of age. The disorder usually is chronic, and the prognosis guarded. Repeated physical examinations help reassure patients that they do not have a fatal illness, but invasive and high-risk diagnostic procedures should be avoided unless medically indicated.

Front 335

341. Alcohol dependence in the elderly

Back 335

Older adults with alcohol dependence usually give a history of excessive drinking that began in young or middle adulthood. They usually are medically ill, primarily with liver disease, and are either divorced, widowed, or are men who never married. Many have arrest records and are numbered among homeless persons. A large number have chronic dementing illness, such as Wernicke's encephalopathy and Korsakoff's syndrome. Of nursing home patients, 20 percent have alcohol dependence.

Over all, alcohol and other substance use disorders account for 10 percent of all emotional problems in older persons, and dependence on such substances as hypnotics, anxiolytics, and narcotics is more common in old age than is generally recognized.

Front 336

342. Clinical presentation of elderly with alcohol dependence or substance use disorders

Back 336

The clinical presentation of older patients with alcohol and other substance use disorders varies and includes confusion, poor personal hygiene, depression, malnutrition, and the effects of exposure and falls.

*The sudden onset of delirium in older persons hospitalized for medical illness is most often caused by alcohol withdrawal.

Alcohol abuse also should be considered in older adults with chronic gastrointestinal problems.

Front 337

343. Elderly and sleep problems

Back 337

Advanced age is the single most important factor associated with the increased prevalence of sleep disorders.

Sleep-related phenomena reported more frequently by older than by younger adults are sleeping problems, daytime sleepiness, daytime napping, and the use of hypnotic drugs. Clinically, older persons experience higher rates of breathing-related sleep disorder and medication-induced movement disorders than younger adults.

Front 338

344. Causes of sleep disturbances in the elderly

Back 338

In addition to altered regulatory and physiological systems, the causes of sleep disturbances in older persons include primary sleep disorders, other mental disorders, general medical disorders, and social and environmental factors.

Among the primary sleep disorders, dyssomnias are the most frequent, especially primary insomnia, nocturnal myoclonus, restless legs syndrome, and sleep apnea.

Of the parasomnias, rapid eye movement (REM) sleep behavior disorder occurs almost exclusively among elderly men.

The conditions that commonly interfere with sleep in older adults also include pain, nocturia, dyspnea, and heartburn.

The lack of a daily structure and of social or vocational responsibilities contributes to poor sleep.

Front 339

345. Changes in sleep structure in the elderly

Back 339

Changes in sleep structure among persons over 65 years of age involve both REM sleep and non-rapid eye movement (NREM) sleep.

The REM changes include the redistribution of REM sleep throughout the night, more REM episodes, shorter REM episodes, and less total REM sleep.

The NREM changes include the decreased amplitude of delta waves, a lower percentage of stages 3 and 4 sleep, and a higher percentage of stages 1 and 2 sleep.

In addition, older persons experience increased awakening after sleep onset.

Front 340

346. Suicide differences between the young and the elderly

Back 340

The most common precipitants of suicide in older individuals are physical illness and loss, whereas problems with employment, finances, and family relationships are more frequent precipitants in younger adults.

Most elderly persons who commit suicide communicate their suicidal thoughts to family or friends before the act of suicide.

Front 341

347. Vertigo and the elderly

Back 341

Feelings of vertigo or dizziness, a common complaint of older adults, cause many older adults to become inactive because they fear falling.

The causes of vertigo vary and include anemia, hypotension, cardiac arrhythmia, cerebrovascular disease, basilar artery insufficiency, middle ear disease, acoustic neuroma, and Meniere's disease.

Most cases of vertigo have a strong psychological component, and clinicians should ascertain any secondary gain from the symptom. The overuse of anxiolytics can cause dizziness and daytime somnolence.

Treatment with meclizine (Antivert), 25 to 100 mg daily, has been successful in many patients with vertigo.

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348. Spousal bereavement in the elderly

Back 342

As a group, older adults appear to have a more favorable outcome than expected following the death of a spouse.

Depressive symptoms peak within the first few months after a death, but decline significantly within a year. A relationship exists between spousal loss and subsequent mortality.

Elderly survivors of spouses who committed suicide are especially vulnerable, as are those with psychiatric illness.

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349. Mini mental status exam

Back 343

The most widely used test of current cognitive functioning is the Mini-Mental State Examination (MMSE), which assesses orientation, attention, calculation, immediate and short-term recall, language, and the ability to follow simple commands.

The MMSE is used to detect impairments, follow the course of an illness, and monitor the patient's treatment responses.

It is not used to make a formal diagnosis.

The maximal MMSE score is 30. Age and educational level influence cognitive performance as measured by the MMSE.

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350. Wechsler Adult Intelligence Scale-Revised (WAIS-R)

Back 344

The assessment of intellectual abilities is performed with the Wechsler Adult Intelligence Scale-Revised (WAIS-R), which gives verbal, performance, and full-scale intelligence quotient (IQ) scores.

Some test results, such as those of vocabulary tests, hold up as aging progresses; results of other tests, such as tests of similarities and digit-symbol substitution, do not.

The performance part of the WAIS-R is a more sensitive indicator of brain damage than the verbal part.

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351. Geriatric Depression Scale

Back 345

Depression, even in the absence of dementia, often impairs psychomotor performance, especially visuospatial functioning and timed motor performance.

The Geriatric Depression Scale is a useful screening instrument that excludes somatic complaints from its list of items.

The presence of somatic complaints on a rating scale tends to confound the diagnosis of a depressive disorder.

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352. Orientation of the elderly

Back 346

Cognitive impairment often is observed in mood disorders, anxiety disorders, factitious disorders, conversion disorder, and personality disorders, especially during periods of severe physical or environmental stress. The examiner should test for orientation to place by asking the patient to describe his or her present location and time.

Greater significance is given to difficulties concerning person than to difficulties of time and place, and more significance is given to orientation to place than to orientation to time.

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353. Prevalence of dementia and Alzheimers

Back 347

The prevalence of dementia in institutional samples is higher than that reported in community samples

The prevalence of Alzheimer's disease is higher among African Americans compared to Caucasians.

In Asian population, approx 60% of the dementias are of the vascular type.

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354. What is the most prevalent anxiety disorder among older adults?

Least prevalent?

Back 348

Phobic disorders are the most common in elders.

Panic disoder is the least common anxiety disorder in this age group.

Overall, anxiety disorder are more common in women than in me. The are less common with increasing age.

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355. What cognitive abilities decline as one ages?

Back 349

In the elderly, simple recall becomes difficult (does not remain intact) and memory-encoding ability diminishes.

However, many cognitive abilities are retained in old age.

Complete learning of new material still occurs.

Also, they maintain their verbal abilities, and their IQs remain stable until approx 80 years of age.

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356. What is the most common metabolic intoxication that causes mental symptoms in the elderly?

Back 350

Uremia, which is an excess of urea and other nitrogenous waste products in the blood.

Mild diabetes, hepatic failure, and gout are also known to cause mental symptoms in the aged as well as alcohol and drug abuse.

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357. Cerebral anoxia

Back 351

Often precipitates mental symptoms as a result of cardiac insufficiency or emphysema. Anoxic confusion may follow surgery, an MI, GI bleeding or occlusion or stenosis of the carotid arteries.

Front 352

358. Verbal memory

Back 352

An ability primarily tied to the left temporal lobe, is typically measured by reading patients a list of words and then having them repeat the words recalled.

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359. Information processing speed

Back 353

Can be measured by having patients rapidly complete rote tasks, such as drawing lines between numbers in sequential order, etc...

Front 354

360. Language skill and word retrieval

Back 354

Language skills are tied to the functions of the left hemisphere;

Word retrieval is measured by having patients provide precise names for pictured objects.

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361. Creutzfeldt-Jacod disease (CJD)

Back 355

One of the transmissible spongiform encephalopathies.

Characterized by progressive dementia and ataxia, not agnosia.

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362. Pick's disease

Back 356

Tau-containing intra-neuronal inclusion bodies (Pick bodies) is associated w/Pick's disease, a progressive dementia characterized by prominent behavioral and language deficits, atrophy of the fronto-temporal region of the brain and ballooned neurons.

Front 357

363. Side effects of antipsychotics in the elderly

Back 357

1. Dry mouth
2. Tardive dyskinesia
3. Akathisia
4. Toxic confusional state

Front 358

364. Abnormalities of cognitive functioning in the elderly are most often due to..?

Back 358

Some cerebral dysfunction or deterioration, although they may also be the result of depressive disturbances, schizophrenia, or the effects of medication.

Hypochondriasis is not the cause of an abnormality of cognitive functioning.

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365. MRI and PET studies of the elderly with Alzheimer's disease

Back 359

MRI studies in Alzheimer's disease show an increased number of T2 hyper-intensities, as well as an increased number of hyper-intensities in peri-ventricular regions. PET studies fin abnormalities in the cerebral metabolic rate for glucose.

Volumetric MRI studies find reductions in the volume of the medial temporal lobe structures, namely the hippocampus and entorhinal cortex, which are correlated w/the severity of cognitive impairment.