Metabolic Bone Disease

Question 1

Bone remodeling

Answer 1

remove older, weaker bone and replacing with newer, stronger bone

• osteoclasts remove by creating resorption pit
• osteoblasts secrete osteoid (bone specific collagen) to fill pits up
• Ca adn Phosphate calcify
• osteoblasts become encased into bone as osteocytes and can sense where sites of stress and can remodel there where bone needed

Question 2

what controls bone resorption

Answer 2

Rank-L; made by osteoblasts

• Binds to RANK on osteoclasts to stimulate resorption by osteoclasts
• bone marrow secretes Osteoprogeterin (OPG) -decoy receptor for RANK-L–binds RANK-L to prevent stimulating osteoclasts
• how much bone resorption depends on how much OPG compared to RANK-L

Question 3

What controls bone formation

Answer 3

Wnt pathway

• aka Frizzled/LRP-5/Beta catenin
• stimulates osteoblasts to make new bone
• Slcerostin = protein in bone inhibiting this pathway/preventing bone formation

Question 4

Osteoporosis

Answer 4

Compromised Bone strength

- predisposes to increased risk for fragility fractures= fractures from no/minimal trauma–standing height or less

Question 5

3 main types fragility fractures

Answer 5

Spine, hip, wrist

Fragility fractures = osteoporosis

Question 6

Risk factors for fragility fractures

Answer 6

Age
Falls
Low bone mass
Previous fractures

Question 7

Osteopenia

Answer 7

T score -1 SD below mean

Question 8

Osteoporosis definition

Answer 8

T score - 2.5 or fragility fracture

Question 9

Risk factors for low bone mass

Answer 9

• Non modifiable: age, race, gender, fam hx, early menopause
• Modifiable: low Ca intake, Low vit D intake, estrogen deficiency, sedentary, cigarette, excess EtOH, excess caffeine, medications (steroids, thyroid hormone excess)

Question 10

does low bone mass mean osteoporosis

Answer 10

NO–large differential

Question 11

meds putting at risk for low bone mass

Answer 11

glucocorticoids, thyroid hormone, anticonvulsants, thiolidinediones, PPIs, SSRIs, SGL-2

Question 12

Prevention/Treat Osteoporosis

Answer 12

Ca: 1000-1500 mg/day (Ca and PO4)
1000 Vit D
Exercise
Falls– prevent

Question 13

pharmacologic idea behind treating osteoporosis

Answer 13

decrease bone reabsorption and increase formation

Question 14

Osteomalacia and Rickets

Answer 14

• O= adults
• R = children
• impaired bone mineralization resulting on soft, weak bones
• Inadequate Ca x Phosphate product for bone mineralization

Question 15

Phosphate Disorders

Answer 15

• Acquired hypophosphatemia (poor oral intake, renal phosphate wasting–can be cause of meds damaging kidneys)
• Congenital hypophosphatemic Ricket’s -95% cases of rickets (Vitamin D resistant Ricket’s– won’t respond to vit D) – have renal phosphate wasting and impaired 1,25 vit D formation

Question 16

hypophosphatemic Rickets

Answer 16

vitamin D resistant

• Renal phosphate wasting
• Impaired 1,25 (OH)2 Vitamin D formation–further reduction in phosphate and Ca
• have to give phosphate and vitamin

Question 17

vit D disorders

Answer 17

• acquired deficiency
• acquired 1,25 vit D def
• Congenital 1 alpha hydroxylase def- vit D dependent Rickets type 2
• Congenital vit D receptor def– vit D dependent Rickets type 2

Question 18

Osteomalacia

Answer 18

• pain typically in long bones
• deformities (soft, tend to bow)
• fractures, pseudofractures (Milkman’s and looser’s lines)

Question 19

RIckets sxs

Answer 19

Proximal muscle weakness, short stature, deformities, pain

- Radiology shows bowing of long bones and flaring of ends of long bones and delayed calcification of epiphyses

Question 20

Paget’s Disease of Bone

Answer 20

idiopathic bone condition
- excessive/unregulated
bone resorption and formation
- biopsy shows thicker, disorganized, weaker, larger, highly vascular
- genetic predisposition and chronic paramyxovirus infection

Question 21

Evidence for Genetic Disorder

Answer 21

• familial aggregation (1540%)
• 18q Linkage– familial expansile osteolysis
• mutation of osteoprotegerin gene = Juvenile Paget’s dz
  so excessive resorption
• Mutation of sequestosome 1/P62 gene found in 40-80% Paget’s families

Question 22

Sequestosome I (SQSTM1/p62)

Answer 22

• controls how osteoclasts develop, work, and undergo apoptosis
• ubiquitin binding protein that forms ubiquitinated chains that function as protein scaffolds for IL-1 and TNF induced NF_kappaB activation, which regulates RANK signalling that controls osteoclast differentiation, activity, and survival

Question 23

STSTMI mutation

Answer 23

linked to Paget’s Disease

Question 24

Viral disorder link in Paget’s

Answer 24

• Geographic variation
• link to dog ownership
• time trends related to measles
• direct viral studies–show paramyxovirus-like inclusions in nuclei - cytoplasm of osteoclasts

Question 25

Unifying hypothesis of Paget's DIsease

Answer 25

Development of Paget's requires: - genetic component enhances osteoclast formation/reactivity - paramyxovirus infection (induces chagnes in osteoclast precursors) -

Question 26

Paget's SXS

Answer 26

Skeletal: Pain, deformity, fractures, osteoarthritis, hypervascularity, acetabular protrusion, osteogenic sarcoma

Question 27

Most common sites of Paget's diseaes

Answer 27

- can be monostotic or polyostotic - Pelvis - Skull - Vertebrae - Femur - Tibuia Neuro: deafness, cranial nerve compression due to compression fo holes nerves travel through (bony), spinal cord compression (vascular) CV: atherosclerosis, aortic stenosis, congestive heart failure (high output)--due to highly vascular bones

Question 28

Clinical course of Paget's Disease of Bone

Answer 28

- initially high osteoclast activity --elevated NTX/CTX, breakdown products of bone - Mixed: about 1- years later, then high osteoclastic and osteoblastic activity; get elevated NTX/CTS as well as Alk Phos from osteoblast activity - osteoblastic: finally like 20 years out, low resorption so low NTX/CTX,below level of formation. Alk phos tends to be high, but may be low after a while

Question 29

Paget's Disease labs

Answer 29

remodeling markers elevated; xray features very specific, bone scan, bone biopsy--occasionally needed

Question 30

Osteolytic lesions on radiology

Answer 30

"blade of grass" sign in long bones; resorption front in flat borne - osteosclerotic lesions near lytic areas thickened, disordered trabeculae thickened, expanded cortex Expansion of bone size

Question 31

Bone scan in Paget's Disease

Answer 31

Focal areas of Intense Uptake when in osteoblastic phase

Question 32

Histology on Paget's

Answer 32

- increased osteoclast numbers/nuclei (20-100 per cell) - increased osteoblasts in periphery - disorganized, mosaic, woven