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Flashcards in MSK Mod 1B Deck (75):
1

Extracellular matrix made up of 2 Components

1. Non-fibrous component
a. Usually gel-like substance…”ground substance”
• Ex: proteoglycans, glycoproteins, minerals, etc…

2. Fibrous component
a. Collagen – provides tensile strength
b. Elastin – provides elastic properties

2

Connective Tissue Composition

A. All connective tissue is composed of a cellular component and extracellular matrix
B. Cellular component
C. Extracellular matrix

3

Bone tissue Composition

A. Bone has cellular and matrix components
1. Cellular: osteoblasts, osteocytes, osteoclasts
2. Matrix: collagen, proteoglycans, BMPs, glcoproteins, growth factors, minerals

4

Osteoblasts are located along: (3)

• trabecular surfaces (cancellous or spongy surface)
• inner surface of haversian’s canal
• inner surface of the periosteum (active bone formation)

5

Osteoblasts Produce numerous substances involved in bone formation/remodeling (3)

• Produces type 1 collagen and non-mineralized bone matrix (osteoid) into immediate area surrounding osteoblast
• Osteoblast also facilitates mineralization (calcification) of osteoid to complete the processs
• Once the surrounding bone matrix (osteoid) is mineralized the osteoblast is now referred to as an osteocyte

6

Osteoblasts (2)

c. Also produce substances that regulate balance of bone formation/resorption

Form new bone

7

Osteocytes

a. Osteocytes are formed from osteoblasts
• After the surrounding bone matrix (osteoid) is mineralized the osteoblast is now referred to as an osteocyte
• The small cavity the osteocyte is located in is known as lacunae
b. Osteocytes make up approximately 90% of the cells in mature human skeleton
c. Osteocytes are not “dead” - they have a blood supply via small capillaries located and are a functionally active cell of bone

8

Osteocyte Functions (5)

• Stimulate remodeling process of bone:
• Serve as sensory mechanism for mechanical stimulus to bone
• Maintain homeostasis of the mineralized (calcification) bone
(i) osteocytes synthesize molecules to assist with bone calcification
(ii) osteocytes receive nutrients from the capillary blood supply which are needed to maintain mineral homeostasis

9

Remodeling Process of Bone (2)

(i) Directly signal steps in bone remodeling
(ii) Assist by secreting enzymes to dissolve surrounding mineralized bone to prepare for bone remodeling

10

Osteoclast mechanism of bone resorption (5)

• Osteoclast secrete acid and lytic enzymes to “breakdown” and dissolve surrounding bone
• Osteoclasts have microvilli (brush border) projecting out from cell
• Elements of bone are resorbed into the osteoclast at the base of the microvilli
• The osteoclast eventually releases the bony elements into the capillaries to allow the elements to be re-cycled into new bone at a different site
• After osteoclastic resoprtion is complete the cell either degenerates or becomes dormant until needed again.

11

Osteoclast Function: resorption of bone (2)

• Break down bone allowing release of calcium into blood stream
• Break down/resorption of inferior (poor quality) bone or surplus bone

12

Osteoclasts are located where? (2)

a. Located in Howship’s lacunae
• Depressions seen in microscopic view that represent areas of bone resorption

13

Collagen Fibers

a. 14 different types of collagen identified in the body
• Type 1 collagen – 90% of collagen in bone is Type 1 collagen
(i) responsible for tensile strength of bones as well as wt bearing (compressive) strength
b. synthesized and secreted by osteoblasts
c. fibers are arranged in fibril network allowing resistance against tensile and compressive forces

14

Proteoglycans (3)

a. Large polysaccharides attached to protein
b. Located between collagen fibers of bone
c. Arrangement and location between collagen fibers also assist in resisting compressive strength of bone

15

Function of Proteoglycans (1)

• Play role in calcification/fluid balance by attracting calcium (via ion exchange)

16

Bone morphic proteins (BMP) and Function (3)

a. Many types BMP-2, BMP-6, BMP-9
b. Function:
• promote formation of osteoblasts from stem cells, osteogenesis in osteoblasts
c. clinical: pharmaceutical intervention strategies for difficult/poor fracture

17

Glycoproteins and Function (3)

a. Many glycoproteins found in bone
• Sialoprotein, laminin, osteonectin, alpha-glycoprotein
b. Function:
• Assist in collagen fiber formation
• May assist in calcification

18

Osteocalcin and Function (2)

a. Produced by osteoblast (part of communication between osteoblasts and osteoclasts)
b. Function: promotes osteoclast activity therefore promotes bone resorption

19

Function of Bone Albumin (2)

• ATTRACTS fluid and maintains fluid balance in bone
• Transports hormones, ions and other metabolites to/from bone cells

20

Growth Factors (cytokines)

• Transforming growth factor (TFG)-beta, TFG – alpha, insulin growth like factor (IGF-1), Tumor necrosing factor (TNF), interleukins, interferon-gamma, etc…

21

Function of Cytokines

• Play role in differentiation, activation, growth and turnover of bone (and other tissue)
c. Example: IGF-1 affects all cells of body & involved in stimulus of long growth (facilitates signaling of GH)

22

Calcium hydroxyapatite (HAP)-- bone mineral

• End stage of calcium crystalization for mineralization (calcification)
• The HAP is an insoluble crystal that deposits within the collagen fibers
• Physical characteristics account for the compressive strength of bone

23

Bone Multicellular Unit (BMU)

1. cluster of cells that breakdown an area of the bone surface and then fills it with new bone
a. multiple BMU clusters are activated/inactivated at any given point in time and in different locations on a bone

24

Origination/activation of BMU-- Bone Remodeling Step 1

• Osteocytes will signal the start of BMU activity
• Stimulus: mechanical stress, trauma, cytokines/hormones or may occur at random
(i) Examples: PTH, IGF, IL-1, IL-6, PGE, calcitriol, TNF, NO

25

Initiation of osteoclastic activity-- Bone Remodeling Step 2

• Pre-osteoblasts are formed and produce RANK-L
(i) RANK-L signal pre-osteoclasts to mature into active osteoclasts
(ii) OPG (osteoprotogerin) inhibits this step
1. OPG is produced by mature osteoblasts

26

Resorption forms small cavity-- Bone Remodeling Step 3

• The osteoclast continues to resorb bone for about two weeks
• eventually undergo pre-programmed death (apoptosis)

27

Bone Remodeling Step 3 Clinical

(i) Estrogen and calcitonin inhibit this step and slow resorption
1. Post menopausal estrogen deficiency prolongs resoprtion and allows osteoclast to keep breaking down bone
(ii) Acidosis promotes osteoclast resorption

28

Osteoblast maturation/ recruitment-- Bone Remodeling Step 4

• Hormones, proteins and other substances promote osteoblast maturation/activity
(i) Examples: PTH, Wnt, BMPs, IGF, FGFs, PDGFs, calcitriol, Runx2, GST-RANK-Ligand, TGF-beta

29

Osteoid Formation-- Bone Remodeling Step 5

• Active osteoblasts secrete collagen and other components of bone matrix

30

Mineralization/maturation of osteoid-- Bone Remodeling Step 6

• Calcium, phosphate and other ions are necessary for mineralization of osteoid
(i) Calcium is crystallized in stages
(ii) Calcium hydroxyapatite (HAP) is final crystallized form that binds to the collagen fibers

31

Bone remodeling is dependent on osteoblast activity coupled with osteoclasts activity (3)

a. The relationship is not fully understood
b. The balance between osteoblasts and osteoclasts determines formation/shape of new bone
c. “Communicator” molecules (cytokine and proteins) between osteoblasts and osteoclasts are new strategies for pharmaceutical intervention to target slow bone loss

32

Bone Reaction to Exercise and Immobilization (3)

a. Wolff’s Law
b. Immobilization/disuse
• Decreased bone density
• Localized osteoporosis
c. Exercise
• Wt bearing/resistance exercise
• Increased bone density

33

Wolff's Law

mechanical stress leads to increased bone density while removal of mechanical stress leads to bone loss

34

Metabolic Diseases of Bone (3)

A. Osteoporosis
B. Osteomalacia
C. Paget’s Disease of Bone

35

Pathologies of Bone (4)

Metabolic Diseases of Bone
B. Osteochondroses
1. Osteonecrosis (avascular necrosis)
2. Apophysitis (epiphysitis)
C. Infection of Bone
D. Tumors of bone and related tissue

36

Osteopenia (2)

a. low BDM (bone mineral density) but not severe enough to be considered osteoporotic
b. a BMD value more 1 SD but less than 2.5 SD below the young adult mean

37

Osteoporosis(2)

a. severe decrease in BMD
b. a BMD value 2.5 SD or more below the young adult mean.

38

Osteomalcia and Osteopetrosis

3. Osteomalcia: “softening” of the bone
4. Osteopetrosis: increase BMD

39

Primary osteoporosis

• generalized decreased bone density unrelated to any underlying disease or condition
• Type 1 – Postmenapausal
(i) Primarily affects cancellous bone
• Type 2 – Age-related
(i) Typical in patients > 75 yrs
(ii) Will see both cancellous and cortical bone loss

40

Secondary Osteoporosis

• Bone density loss secondary to medication or disease

41

3 Phases of Bone Mass

• Growth phase
• Consolidation phase
• Involution phase
(i) Gradual loss of bone density is multi-factorial
1. normal and pathological causes

42

Growth Phase of Bone Mass (2)

(i) Continues until growth plates closed
(ii) 90% of bone density is reached in growth phase

43

Consolidation Phase of Bone Mass (2)

(i) Bone density continues to increase until reaches peak bone mass
(ii) Remaining 10% of bone density occurs during this phase

44

Peak Bone Mass (PBM)

• Bone formation occurs at faster rate than bone resorption
• Peak bone mass is commonly reached by 30 yrs of age
(i) Short plateau of peak bone mass – approximately 3-5 years
(ii) Clinical: poor dietary/exercise lifestyle in teens/20’s result in lower peak bone mass

45

Age Related Bone Mass

“normal” bone loss with age
(i) Bone loss in men/women usually begins 35-40 yrs of age following a short plateau of bone density during early 30’s
(ii) Rate of age related bone loss
1. age related rate of bone density loss is fairly equal between male and female
2. men start out at higher PBM so don’t reached osteoporotic level as soon as women
(iii) men/women loss approximately 0.5 - 1% per year due to normal age related bone loss

46

Post-menopausal bone loss

(i) rate of bone loss in women is accelerated after menopause
1. decreased estrogen levels associated with post menopause causes increased rate of bone density loss
a. estrogen has protective effect on bone density
(ii) during 1st decade following menopause rate of bone loss accelerates
1. rate of loss may increase to 3-5% per year
2. 15% of total bone mass may be lost during 1st decade post menopause
a. This is approximately 40-50% of the total expected lifetime bone density loss of a female
(iii) rate gradual slows down after the 1st decade

47

Post-menopausal pathogenesis of osteoporosis

(i) Estrogen loss disrupts RANK-L (promotes osteoclast maturation) and OPG (inhibits osetoclast maturation) homeostasis
1. higher levels of RANK-L with reduced levels of OPG
2. Clinical: drug – raloxifene stimulates OPG production
(ii) Regions: most significant in cancellous (trabecular) bone
1. vertebra, metaphysic of long bone (wrist and femur common fracture sites)

48

Age Related pathogenesis of osteoporosis

(i) Numerous age related factors suggested to contribute
1. Decreased GH and IGF levels
2. Decreased androgens
3. Increased RANK-L and inhibited OPG
4. lifestyle – poor nutrition and inactivity
a. osteocytes are stimulated with mechanical stress
b. poor vitamin D, calcium and other nutrients

49

Medications that can cause osteoporosis

• Medications
(i) Corticosteroids and immunosuppressants can alter RANK-L and OPG balance

• Other metabolic/systemic disorders
(i) Ex: RA, metastatic cancer also alter RANK-L and OPG balance

50

Trabecular Bone

(i) Trabecular bone very sensitive to conditions that alter osteoblast & osteoclast activity
1. Why? Large surface area and not “large bone mass” to begin with compared to cortical bone
(ii) Percent of trabecular loss greater than cortical loss
(iii) Trabecular bone more sensitive to post-menopausal bone loss vs age related loss

51

Bone loss of men to women

1. women may lose up to:
a. 35–50% of trabecular bone mass
b. 25–30% of cortical bone mass
2. men may lose up to:
a. 15–45% of trabecular bone mass
b. 5–15% of cortical bone bone mass

52

Osteoporosis Risk Factors

a. Hormonal status
b. Physical Inactivity
c. Genetics/ethnicity
d. Medications
e. Tobacco
f. Alcohol
• Alcohol impairs osteoblast activity
• Alcohol also impairs calcium absorption and increase renal excretion of calcium
g. Diet and Nutrition

53

Hormonal Status

• Post-menopausal women have decrease estrogen levels
• 5 – 8 years after menopause women have accelerated bone lose rate (i.e. greater than 1% per year)…HRT most effective during this time period
• Men have much more gradual loss of testosterone thus have slower steady rate bone los

54

Physical Inactivity

• Throughout all phases of the lifespan
• Low activity in age groups < 25 yrs have decreased peak bone mass
• Excessive activity combined with eating disorder can increase risk of osteoporosis

55

Medications for osteoporosis Risk Factors

• Corticosteroid
• Long term corticosteroid use will decrease bone mass
• Large loss occurs during first six months of use…then rate slows
• Corticosteroids impair osteoblasts and increase osteoclast activity

56

Diet and Nutrition for osteoporosis risk factors

• Low calcium intake in growing years
• Anorexia/bulemia in females
(i) Amenorrhea & reduced estrogen
(ii) Female triad…eating disorder, amenorrhea, osteoporosis

57

BMD Test for Osteoporosis Eval

• average of thousands of 30 yr old females used as the baseline T score
• Statistical technique to measure the number of standard deviations from the population average
• A decrease in 1 SD will increase risk of fracture by 1.5 – 3x’s
(i) normal: a BMD ≤ 1 SD of the young adult mean
(ii) osteopenia: a BMD value > 1 SD but < 2.5 SD below the young adult mean
(iii) osteoporosis: a BMD value > 2.5 SD below the young adult mean

58

Types of BMD Tests

• Dual energy x-ray absorptiometry (DEXA or DXA)
(i) Considered “gold standard”
(ii) DEXA alone does not help identify individuals who have greater risk of fractures
1. i.e. SD might be equal in two people but one more susceptible to fracture
• Single photon absorptiometry
• Dual photon absorptiometry
• Quantitative US
• CT
• NOTE: Plain film x-ray
(i) Poor screening tool: only detects bone loss after significant loss has occurred

59

Etiology of Osteomalacia

a. Poor nutrition…i.e. poor vit D intake
b. Intestinal disease that impairs absorption
c. Renal disease
d. Medications
e. Tumors

60

Osteomalacia

1. Insufficient mineralization of bone
a. No loss of bone….matrix just doesn’t mineralize
3. X-ray
a. "Looser's zones" or Milkman's pseudofractures. These lesions are composed of poorly mineralized osteoid matrix and are not true fractures or stress fractures. They are oriented perpendicular to the long axis of the bone, and do not cross the entire bone
b. Bowing of long bones
4. Rickets = “childhood osteomalcia”

61

Potential Complications of Pagets Disease of Bone

a. Fracture
b. Deformity
c. Arthritis
d. Nerve dysfunction if compressed in skull
e. Pain

62

Pathology of Paget's Disease

a. Distortion of bone resorption and formation of trabecular bone
b. Communication between osteoblasts and osteoclasts are altered
c. Excessive resorption is followed by excessive bone formation
• Result: enlarged deformed bone of poor quality
• Disorganized collagen fibers, poor mineralization, etc…
d. Eventually become inactive

63

Paget's Disease of Bone

1. Disease that results in bone deformation with associated complications
2. Onset > 50 yrs most common
3. M>F (8:1 ratio)

64

Clinical Signs of Osteonecrosis

a. Early – often no symptoms
b. Chronic – gradual onset of pain
c. If fracture – acute onset of pain

65

Common Sites of Osteonecrosis

(i) Femoral head = most common site
(ii) Scaphoid
(iii) Proximal humerus
(iv) Tibial plateau
(v) Small bones of wrist/ankle

66

Osteonecrosis (avascular necrosis – AVN)

1. Death of bone due to loss of blood supply
2. Fracture or other pathology that disrupts the blood flow to the bone

67

Common Causes of AVN

a. Post-traumatic
b. Steroid use
c. Alcohol use
d. Idiopathic

68

Apophysitis

1. Apophysitis = a traction apophysitis of the secondary ossification center
a. Osgood-Schlatter disease
b. Patella tendon pulling on tibial tuberosity
c. Olecranon apophysitis
• Young throwing athletes…triceps tendon pulling on secondary ossification center of olecronon
d. Sever’s disease
• Achille’s tendon pulling on the secondary ossification center of the calcaneous

69

4 Terms associated with osteomyelitis

1. Acute osteomyelitis:
a. New episode of infection
2. Chronic osteomyelitis:
a. Ineffective or delayed treatment with relapsing episodes
3. Exogenous osteomyelitis
a. Trauma exposes bone to bacteria and other foreign
4. Hematogenous osteomylitis
a. Infection spread to bone from pre-existing systemic infection
b. Etiology - staphylococcus aureus is common cause of endogenous (hematogenous)

70

Pathology of Osteomyelitis

1. Physical arrangement of bone (micro-channels) contains regions that immune defense mechanisms unable to access
2. This makes bone susceptible to infection if bacteria (or foreign invader) gains access
3. Inflammation response similar to any other infection: impairs BV, lymph vessels in area

71

Pathology of Osteomyelitis is Adults and Children

a. Adults:
• Inflammation eventually causes disruption of bone cortex
• Potential for pathological fracture

b. Children: sequestrum and involucrum formation
• Inflammation may “lift off” periosteum from sub-periosteal abscess and more disruption of blood supply
• Necrosis of bone occurs producing a sequestrum
• “Lifting off” of periosteum causes increase in osteoblastic activity resulting in new bone growth (involucrum formation)

72

Clinical Osteomyelitis – adults vs children

1. Anatomical location
a. Adults: lumbar spine
b. Children: metaphysis near growth plate in long bones
• Distal femur, proximal humerus, tibia, radius

2. Signs/symptoms
a. Adults – back pain with lower grade fever
b. Children – high fever and local pain, redness, swelling

73

Primary Benign Bone Tumors

1. Well-differentiated, tend to be slower growing
2. Bone responds by attempting to contain…form sclerotic rim
3. Do not tend to produce constant progressive bone pain that is typical of malignant bone tumors

74

Primary Malignant Bone Tumors

1. Aggressive, faster growing with capacity to spread to other areas
2. Aggressive growth often expands beyond cortical limits of the bone…damaging adjacent soft tissue as well
3. Bone can’t mount a response to contain tumor
4. Potential to metastasize

75

patterns of bone destruction

a. geographic
• Well defined margins surrounding clear lytic area
b. moth eaten
• less defined margins, surrounding lytic or partially lytic area
c. permeative
• poorly defined margins; abnormal lytic bone merged throughout bone