Phar 471 - Osteoporosis

Front 1

What is the definition of Osteoporosis?

Back 1

A skeletal disorder characterized by compromised bone strength, pre-disposing a person to an increased risk of fractures

Front 2

What factors contribute to Bone Strength?

Back 2

1) Bone Mineral Density (BMD)

2) Bone Quality (Rate of Turnover, Mineralization, Micro-architecture)

Front 3

What are the components of bone?

Back 3

i) Organic (30%):

1) Cells (2%); Osetoblasts, Osteocytes, Osteoclasts

2) Matrix (98%); Collagen Type 1, Bone Proteoglycan

ii) Minerals (70%): Hydroxyapatite and other minerals

Front 4

What are the types of Bone?

Back 4

Cortical (compact) and Trabecular (Cancellous)

Front 5

What are the characteristics of Cortical (compact) bone?

Back 5

1) Dense and Solid with few spaces

2) Surrounds the marrow space

3) Mainly mechanical and protective function

4) Makes up 80% of adult skeleton

Front 6

What are the characteristics of Trabecular (cancellous) bone?

Back 6

1) Mesh-like bone located in the center of the bone

2) Much larger % of surface area in contact with bone marrow, blood vessels

3) Both metabolic AND mechanical function

4) Makes up 20% of adult human skeleton

5) More active, subject to more remodelling and turnover

Front 7

Which parts of the skeleton have more trabecular than cortical bone?

Back 7

Vertebrae

Front 8

Which parts of the skeleton have more cortical than trabecular bone?

Back 8

Forearm and Femoral Neck

Front 9

Which parts of the skeleton have equal portion of cortical and trabecular bone?

Back 9

Trochanteric Region (hip)

Front 10

What are the functions of Bone?

Back 10

1) Mechanical: (protects internal organs and acts as a site of insertion for muscles and joints)

2) Metabolic: (mineral reservoir for calcium and phosphate homeostasis)

3) Hematopesis: (Bone marrow is the site of blood cell production)

Front 11

What is the definition of Bone Remodelling?

Back 11

The continous coupled process of bone breakdown and renewal

Front 12

What are the functions of Bone Remodelling?

Back 12

1) Repair areas of micro-damage to the skeleton

2) Maintain skeletal mass

3) Participate in regulation of Calcium Homeostasis

Front 13

What are the functions of Osteoclasts?

Back 13

To resorb bone

Front 14

What are the functions of Osteoblasts?

Back 14

To form new bone matrix (osteoid)

Front 15

What are the functions of Osteocytes?

Back 15

Mechanoreceptors/ Effectors embedded in bone

Front 16

What are the functions of Lining Cells?

Back 16

Have receptors for hormones and factors that initiate remodelling and has a role in recruiting and activating osteoclasts.

Front 17

Which of the bone cells are formed from large multi-nucleated cells from Hematopetic precursors?

Back 17

Osteoclasts

Front 18

Which of the bone cells are formed from local mesenchymal stem cells?

Back 18

Osteoblasts

Front 19

Which of the bone cells are formed from osteoblasts trapped within the bone they're formed from?

Back 19

Osteocytes

Front 20

Which of the bone cells are formed from osteoblasts that remain on the surface of the bone?

Back 20

Lining Cells (Osteoblastic Stromal Cells)

Front 21

What are the steps of the bone remodelling cycle?

Back 21

1) Activation: Initiating the Cycle

2) Resorption by Osetoclasts

3) Reversal

4) Bone Formation

Front 22

How does the process of activation of happen in the bone remodelling cycle?

Back 22

1) Osteoblastic stromal cells begin to produce factors (e.g. macrophage colony stimulating factor and RANK-Ligand) that binds to osetoclast precursors

2) This initiates their replication and differentiation into multi-nucleated functional Osteoclasts

3) Circulating T-Lymphcytes and Bone Lining Cells may also participate in the process of Osteoclast Activation

Front 23

What are the proteins involved in regulating Osteoclast activation?

Back 23

RANK-Ligand and Osteoprogerin (OPG)

Front 24

What is the role of RANKL in regulating Osteoclast activation?

Back 24

Binds to receptor (RANK) on pre-osteoclasts. Stimulates their development into fully differentiated osteoclasts and increases their activity

Front 25

What is the role of OPG in regulating Osteoclast activation?

Back 25

Binds to RANK-Ligand and prevents its interaction with RANK.

This opposes the differentiation and activation of Osteoclasts.

Front 26

What factors increase the ratio of RANKL/OPG? What effect does this have?

Back 26

Parathyroid Hormone, Vitamin D and Some Cytokines.

Increases Osteoclast activity and bone resorption.

Front 27

What factors decrease the ratio of RANKL/OPG? What effect does this have?

Back 27

Estrogen, TGF-β and Mechanical Force.

Decreases Osteoclast activity and bone resorption.

Front 28

How do Oseoclasts perform resorption?

Back 28

1) Osteoclasts attach to the bone and integrins and forms a ruffled border

2) H+ is generated by the action of intracellular Carbonic Anhydrase II (CAII) is actively transported across the membrane of the ruffled border by the "H-ATPase proton pump".

3) A chloride channel coupled to the proton pump balances the charge of ions across the membrane

4) The organic matrix of the bone is removed by proteases such as Cathepsins and Collagenases

Front 29

What happens after Bone Resorption and before Bone Formation?

Back 29

1) After resorption is complete; Osteoclasts detach and undergo Apoptosis

2) Other mononuclear cells cover the surface and form a cement line

3) This marks the limit of bone resorption and cements together the old and new bone

Front 30

What are the steps of Bone formation?

Back 30

1) Mesenchymal stem cells are recruited and differentiate into pre-osteoblasts (by factors such as IGF-1 and TGF-β) there they proliferate and differentiate into mature osteoblasts

2) Osteoblasts secrete proteins of the bone matrix (osteoid) largely collagen. Unmineralized osteoid slowly re-fills the cavity

3) During this process some Osteoblasts become trapped in the newly formed Osteoid (to become Osteocytes)

4) Some osteoblasts undergo apoptosis and others become lining cells

5) Mineralization of bone with Hydroxyapatite then takes place

Front 31

What are examples of Bone Remodelling Cycle Activators?

Back 31

Parathyroid Hormone (PTH), Vitamin D, Thyroid Hormones, Interleukins and TNF-α

Front 32

What are examples of Bone Remodelling Inhibitors?

Back 32

Calcitonin and Estrogen

Front 33

How does bone mass change with age in men and in women?

Back 33

Generally increases with age and levels off at around 35-40 yrs, and begins to decrease with age.

Women decrease more rapidly with the loss of Estrogen

Front 34

What factors affect peak bone mass?

Back 34

1) Heredity 2) Mechanical Forces

3) Gender 4) Hormones

5) Nutrition 6) Risk Factors

Front 35

What are the mechanisms of AGE related bone loss?

Back 35

1) Rate of initiation of bone remodelling cycles increases

2) Slight imbalance between Osteoclast and Osteoblast activity in each remodelling cycle (more bone is resorbed than formed again)

Front 36

What are the effects of Estrogen on bone remodelling?

Back 36

i) Inhibits Osteoclast Precursors (reduced differentiation and activation)

ii) Inhibits Osteoclasts (decreased activity, increased apoptosis)

iii) Increased Osteoblast lifespan and anabolic activity

Front 37

What are the mechanisms of ESTROGEN deficient bone loss?

Back 37

1) Increased Osteoclast Activation and recruitment of increased BMU activation frequency

2) Reduced Osteoclast Apoptosis

3) Decreased activity and increased apoptosis of Osetoblasts

Front 38

What are the effects of Glucocorticoids on bone remodelling?

Back 38

Rate of bone density loss is estimated to be 10-30%/year.

Bone density loss begins within first 3 months of use, peaks at 6 months and then drops to a slower steady rate.

Front 39

What are the mechanisms of GC-induced bone loss?

Back 39

1) Inhibition of intestinal Ca absorption and increased urinary Ca loss

2) Direct Stimulation of bone resorption via increased RANKL expression

3) Decreased Osteoblast mediated bone formation

4) High dose of GCs also suppress Gonadotropin production

Front 40

What are the effects of accelerated bone loss on bones?

Back 40

i) Cortical Bone becomes thinner and more porous

ii) Trabecular bone becomes weaker (due to decreased bone density, increased number of resorption pits, loss of trabecular connectivity)

Front 41

"Thinning and eventual loss of trabecular connectivity in greatly weakened bones" True or False?

Back 41

TRUE

Front 42

What type of osteoporosis is associated with disproportionate loss of trabecular bone?

Back 42

Post-Menopausal

Front 43

What type of osteoporosis is associated with slower, steady loss of bone, proportionally from cortical and trabecular sites?

Back 43

Age Assoicated

Front 44

What are the common fracture sites of Post Menopausal Osteoporosis?

Back 44

Vertebral body and Distal Radius (wrist)

Front 45

What are the common fracture sites of Age Associated Osteoporosis?

Back 45

Vertebral body and Proximal Femur (Hip)

Front 46

What are the characteristics of Vertebral Body fractures?

Back 46

Most common type of fracture.

Up to 2/3 are asymptomatic but acute fractures are often very painful.

Results in loss of height and curvature of spine.

Front 47

What are the characteristics of Hip Body fractures?

Back 47

Most serious type of fracture.

Occurs more commonly in women than men over 80.

Associated with 20-30% mortality within 1 year.

Front 48

What are the characteristics of Wrist fractures?

Back 48

Also known as the Colles fracture

Front 49

What are "Crash Fractures"?

Back 49

Whole vertebrae gives out and collapses

Front 50

What are "Wedge Fractures"?

Back 50

One side of the vertebrae collapes but not the other side

Front 51

What are "Codfishing Fractures"?

Back 51

The center of the vertebrae collapes but the sides remain upright

Front 52

"Most hip fractures occur in the area just above the ball of the femur" True or False?

Back 52

False; Usually it is just below the ball of the femur (femoral neck region) and the area just below this (interochanteric region)

Front 53

What are the techniques used for measuring BMD?

Back 53

1) Dual Energy X-ray Absorptiometry (DEXA)

2) Single Energy X-ray Absorptiometry (SEXA)

3) Quantitative Computed Tomography (QCT)

4) Ultrasonography

Front 54

What are the common sites of measuring BMD with a DEXA scan?

Back 54

Lumbar spine and Proximal Femur

Front 55

What are the common sites of measuring BMD with a SEXA scan?

Back 55

Forearm and Heel

Front 56

What are the common sites of measuring BMD with a QCT scan?

Back 56

Spine

Front 57

What are the common sites of measuring BMD with an Ultrasonography?

Back 57

Heel, Fingers, Tibia, Patella

Front 58

What are the characteristics of a DEXA scan?

Back 58

1) Precise

2) Low Radiation Exposure

3) Needs Skilled Operator

4) Currentlty the gold standard

Front 59

What are the characteristics of a SEXA scan?

Back 59

1) Inexpensive

2) Measures sites unresponsive to therapy

3) Does not need skilled operator

Front 60

What are the characteristics of a QCT scan?

Back 60

1) Poor reproducibility outside experienced labs

2) Accuracy comparable to DEXA

3) More expensive than DEXA

Front 61

What are the characteristics of Ultrasonography?

Back 61

1) Inexpensive

2) Less Precise

3) Fairly Portable

Front 62

What is the mechanism of a DEXA scan?

Back 62

X-rays from two different sources directed towards bone in alternating pattern.

As the emitted photons pass through the subject's tissues they are attenuated to an extent that depends on the tissues mineralization

Front 63

How does the WHO define Osteoporosis?

Back 63

Based on comparison of patients BMD with the mean BMD obtained in a healthy, young adult populations

Front 64

What is the definition of the "T-score"?

Back 64

The number of standard deviations below or above the mean BMD of the young healthy adult population

Front 65

What is definition of Normal Bone?

Back 65

T-score greater than or equal to -1.0

Front 66

What is the definition of Osteopenia?

Back 66

T-score between -1.0 and -2.5

Front 67

What is the definition of Osteoporosis?

Back 67

T-score less than -2.5

Front 68

What is the definition of established (severe) Osteoporosis?

Back 68

Includes the presence of a non-traumatic fracture

Front 69

"For every 1 standard deviation decrease in BMD; the risk of fracture increases by ___"

Back 69

2

Front 70

"For the same level of BMD, 80 year olds have the same fracture risk as 60 year olds" True or False?

Back 70

False; For the same level of BMD, 80 year olds have 5 times increased fracture risk when compared with 60 year olds

Front 71

What are the major risk factors fro Osteoporotic Fractures?

Back 71

1) Age >65

2) Personal history of Fragility fractures

3) Systemic glucocorticoid therapy for more than 3 months

4) First degree relative with Osteoporotic fracture

5) Hypogonadism

6) Early Menopause (before age 45)

7) Pre-disposing medical conditions such as malabsorption and hyperparathyroidism

Front 72

What are the minor risk factors for Osteoporotic Fractures?

Back 72

1) Past history of clinical hyperparathyroidism

2) Chronic Anti-convulsant therapy

3) Low dietary calcium intake

4) Smoking

5) Excessive Alcohol intake

6) Excessive Caffeine intake (>4 cups coffee/day)

7) Weight <57kg

8) Short term weight loss >10% from weight at age 25

9) Chronic Heparin Therapy

10) Rheumatoid Arthritis

Front 73

What are the current BC health guidelines for when to recommend measuring BMD?

Back 73

Patients who have at least ONE MAJOR (or TWO MINOR) risk factors for Osteoporosis AND if the results are likely to Alter Patient Care

Front 74

What are the only groups of patients you would re-measure BMD within one year?

Back 74

1) Patients receiving >7.5mg Prednisone equivalents for more than 3 months

2) Patients with very low BMD

3) Patients with existing fractures