Metabolic Bone Disease Flashcards
Bone remodeling
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
what controls bone resorption
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
What controls bone formation
Wnt pathway
- aka Frizzled/LRP-5/Beta catenin
- stimulates osteoblasts to make new bone
- Slcerostin = protein in bone inhibiting this pathway/preventing bone formation
Osteoporosis
Compromised Bone strength
- predisposes to increased risk for fragility fractures= fractures from no/minimal trauma–standing height or less
3 main types fragility fractures
Spine, hip, wrist
Fragility fractures = osteoporosis
Risk factors for fragility fractures
Age
Falls
Low bone mass
Previous fractures
Osteopenia
T score -1 SD below mean
Osteoporosis definition
T score - 2.5 or fragility fracture
Risk factors for low bone mass
- 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)
does low bone mass mean osteoporosis
NO–large differential
meds putting at risk for low bone mass
glucocorticoids, thyroid hormone, anticonvulsants, thiolidinediones, PPIs, SSRIs, SGL-2
Prevention/Treat Osteoporosis
Ca: 1000-1500 mg/day (Ca and PO4)
1000 Vit D
Exercise
Falls– prevent
pharmacologic idea behind treating osteoporosis
decrease bone reabsorption and increase formation
Osteomalacia and Rickets
- O= adults
- R = children
- impaired bone mineralization resulting on soft, weak bones
- Inadequate Ca x Phosphate product for bone mineralization
Phosphate Disorders
- 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
hypophosphatemic Rickets
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
vit D disorders
- 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
Osteomalacia
- pain typically in long bones
- deformities (soft, tend to bow)
- fractures, pseudofractures (Milkman’s and looser’s lines)
RIckets sxs
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
Paget’s Disease of Bone
idiopathic bone condition
- excessive/unregulated
bone resorption and formation
- biopsy shows thicker, disorganized, weaker, larger, highly vascular
- genetic predisposition and chronic paramyxovirus infection
Evidence for Genetic Disorder
- 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
Sequestosome I (SQSTM1/p62)
- 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
STSTMI mutation
linked to Paget’s Disease
Viral disorder link in Paget’s
- Geographic variation
- link to dog ownership
- time trends related to measles
- direct viral studies–show paramyxovirus-like inclusions in nuclei - cytoplasm of osteoclasts
Unifying hypothesis of Paget’s DIsease
Development of Paget’s requires:
- genetic component enhances osteoclast formation/reactivity
- paramyxovirus infection (induces chagnes in osteoclast precursors)
-
Paget’s SXS
Skeletal: Pain, deformity, fractures, osteoarthritis, hypervascularity, acetabular protrusion, osteogenic sarcoma
Most common sites of Paget’s diseaes
- 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
Clinical course of Paget’s Disease of Bone
- 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
Paget’s Disease labs
remodeling markers elevated; xray features very specific, bone scan, bone biopsy–occasionally needed
Osteolytic lesions on radiology
“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
Bone scan in Paget’s Disease
Focal areas of Intense Uptake when in osteoblastic phase
Histology on Paget’s
- increased osteoclast numbers/nuclei (20-100 per cell)
- increased osteoblasts in periphery
- disorganized, mosaic, woven
