bone disorders/osteoporosis (Praveen) Flashcards
What is the outer layer of a bone called?
cortex
What is the inner layer of bone?
trabeculae
- spongy, loose meshed lattice of thin strands
Where is bone marrow located?
in the spaces between the trabeculae
What does bone marrow contain?
fat and blood forming tissue
What is the end of a bone called?
epiphysis
What is cortical bone made from/found?
Haversian system (blood vessels in centre, osteocytes) outside of bone
2 types of bone
cortical
trabesular
What is on the ends of long bone?
articluar cartilage
What type of tissue is bone?
specialised connective tissue
minerals in bone
calcium phosphate salts
calcium carbonate
3 cells in bone
osteoblasts
osteocytes
osteoclasts
3 types of joints
fibrous
cartilaginous
synovial
What are osteoblasts?
active bone forming cells
produce collagenase bone matrix
secrete enzyme alkaline phosphatase - promotes deposition of Ca phosphate salts in the matrix to calcify the bone
What do osteoblasts secrete?
enzyme alkaline phosphatase
-> promotes deposition of Ca phosphate salts to calcify the bone
What are osteocytes?
inactive mature bone cells
- as bone matrix is formed/calcified, osteoblasts become incorporated within the bone and are transformed into osteocytes
- maintains bone tissue
What are osteoclasts?
multineucleated cells
bone resorption
remove bone matrix by phagocytosis
dissolve bone salts and release Ca and phosphate ions in circulation
What is the osteoclast differentiation factor?
RANK-L (ligand)
What does RANKL bind to?
RANK
Where is RANK receptor located?
on osteoclast precursors
What causes osteoclast precursors to differentiate into mature osteoclasts?
RANKL-RANK binding interaction and M-CSF (macrophage colony stimulating factor)
What is released as mature osteoclasts resorb bone?
TGF beta
IGF-1
growth factors
cytokines
What do the released factors from osteoclast resorption stimulate? (TGF beta, IGF1, GF, cytokines)
they stimulate osteoblast precursors to develop into mature osteoblasts
these refill the resorption cavaties that osteoclasts left
What causes osteoblast precursors to express RANKL?
PTH
shear stress
TGF beta
What accelerates bone loss in women?
oestrogen deficiency
hormones that influence bone formation/metabolism
PTH calcitonin oestrogen androgen GH glucocorticoids thyroid hormone
local regulators of bone remodelling
cytokines - IL6, IL1
prostaglandins
growth factors - IGF1, TGF beta
4 metabolic bone diseases
osteoporosis
Pagent’s disease
osteomalacia
Rickets
presentation of osteoporosis
back pain
loss of height
fracture
presentation of Pagent’s disease
deformity of long bones
pain in hips
presentation of osteomalacia
generalised bone pain
muscle weakness
definition of osteoporosis
skeletal disorder characterised by the loss of bone mass and deterioration of the bone tissue with an increase in bone fragility and susceptibility to fractures
causes of osteoporosis
endocrine disorder malignancy postmenopausal women taking LT oral corticosteroids aging process
5 causes of osteoporosis in general
genetic reduced physical activity reduced nutrition menopause aging
How does menopause cause osteoporosis?
decrease in oestrogen
incresed IL-1, IL-6 and TNF levels
increased expression of RANK, RANKL
increased osteoclast activity
How does aging cause osteoporosis?
decreaed replicative activity of osteoprogenitor cells
decreased synthetic activity of osteoblasts
decreased biologic activity of matrix-bound growth factors
reduced physical activity
basic pathophysiology of OP
- inc in cytokines act OC
- longer lifespan of OC (dec apoptosis)
- shorter lifespan of OB (inc apoptosis)
- shorter lifespan of osteocytes
-> all lead to larger resorptive cavities in bone, bone more fragile, #
What does deeper/larger resorption cavities in bone lead to?
bone is more fragile
bone fractures
risk factors associated with osteoporosis
personal - aging female - small bone structure - postmenopasual - FH lifestyle: - sedentary - vit D deficiency - low Ca intake - high protein diet - excessive alcohol/caffiene - smoking - drug related - diet related
diseases/conditions that cause reduction in bone mass
Cushing's syndrome hyperthyroidism hyperparathyroidism Coeliac disease (gluten sensitive enteropathy) IBD
drugs that can increase risk of osteoporosis
oral glucocorticoids pioglitazone (TZDs) PPIs cancer treatments (radiation/chemo) thyroxine antiepileptic - phenytion/CMZ gonadal hormone suppression - medroxyprog immunosuppressive agents
When should an assessment for fracture risk be done?
all women >65 yrs
all men >75 yrs
-> or under these ages with a risk factor
What are risk factors for women <65 and men < 75?
- previous fragility #
- current/frequent use of steroids
- Hx of falls
- FH of hip fracture
- causes of secondary osteoporosis
- low BMI (<18.5)
- smoking
- alcohol > 14 units/week women, > 21 for men
indicators of low bone mineral density
low BMI < 18.5 ankylosing spondylitis (spine inflamed) Crohn's disease conditions resulting in prolonged immobility untreated premature menopause
When do you assess fracture risk in under 50 yrs?
if they have major risk factors
- current/frequent use of oral/systemic steroids
- untreated premature menopause
- previous fragility fracture
What test is used to measure BMD (bone mineral density)?
DEXA scan
What do DEXA BMD values mean?
higher BMD value - more bone mineral present
How is BMD measured?
Z score - compared to the expected BMD for patient’s age/sex
T score - compared to young adults of the same sex
What does DEXA stand for?
dual energy x-ray absorptiometry
Where does DEXA scan in the body?
spine and hip
What can DEXA diagnose?
osoteopenia - mild/moderate bone loss
osteoporosis - severe bone loss
osteopenia T score
between -1.0 and -2.5
T score for osteoporosis
less than -2.5
T scores for normal BMD
between 2.5 and -1
What do T score values above 2.5 on DXA scan indicate?
high bone mass
eg. ostroarthritis
(artifically raises bone mineral mass)
1st step if patient has clinical risk factors with/without FRAX analysis
low risk - reassure
mod/high risk - measure BMD at hip and spine
1st step if patient over 55 has fragility fracture
measure BMD at spine and hip
What to do after BMD measurement?
normal (>1) - reassure
osteopenia (-1.5 to -2.5) - lifestyle advice, reassess after 2-5yrs
osteoporosis (< -2.5) - lifestyle advice and drug treatment
factors for prevention of osteoporosis
- regular exercise
- adequate Ca intake
- oral bisphosphonates (postmenopausal)
- maintenance of bone mass - weight bearing exercises (walking/jogging/rowing/weight lifting)
When is treatment given for osteoporosis?
BMD < -2.5
BMD < -1.5 in steroid induced
treatment for patients with vertebral fracture (BMD doesn’t matter)
examples of bisphosphonates
alendronate
etidronate
risedronate
How do bisphosphonates work?
inhibitors of bone resorption and increse BMD by altering osteoclast activation and function
incorporate into ATP analogues that accumulate within the osteoclasts and promote their apoptosis
What are bisphosphonates similar to?
pyrophosphate
How do potent amino-bisphosphates work?
prevent bone resorption by interfering with the cell surface proteins on the osteoclast membrane by prenylation
preventing osteoclast attachment to bone
examples of oral bisphosphonates
alendronic acid
ibandronic acid
risedronate sodium
When are oral bisphosphonates only recommended?
- patient eligible for risk assessment (w O65, mO75 or under with risk factors)
- 10yr probability os osteoporotic fragility fracture is at least 1%
When are IV bisphosphonates used?
- eligible for risk assessment
- 10yr probability of osteoporotic fragility at least 10%
- 10yr probability at least 1% and difficulty taking oral bisphosphonates/ci/not tolerated
examples of IV bisphosphonates
ibandronic acid
zoledronic acid
How to take oral bisphosphonates
on empty stomach
with water only
no food/drink/meds for 30 mins after
don’t lie down for 30mins after alendronic acid (irritate oesophagus/GI s/e)
s/e with oral bisphosphonates
upper GI disturbances (10% pts)
dose adjustments with oral bisphosphonates
renal impariment
alendronic acid avoided if eGFR <35
- nephrotoxicity risk
oral bisphosphonates and hepaic impairment
use zoledronic acid with caution in severe hepatic impairment
What bisphosphonates to use with glucocorticoid osteoporosis?
alendronic acid
risedronate
What bisphosphonates to use with hypercalcaemia of malignancy?
IV zoledronic acid
pamidromate
What bisphosphonates to use with Pagent’s disease?
zoledronic acid
oral risedronate
What bisphosphonates to use with bone metastases?
IV pamidronate
oral ibandronic acid
s/e with bisphosphonates
oespohageal irritation flu-like syndrome GI disturbances headache MSK pain
bisphosphonates drug interactions
reduced absorption of bisphosphonates with
- antacids
- Ca salts
- Fe supplements
What to give if intolerant/ci to oral bisphosphonates?
IV zoledronic acid or teriparatide
dose of IV zoledronic acid
5mg once per year
SERM
selective ostreogen receptor modulator
example of SERM
Raloxifene
How does raloxifene work?
selective agonist or antagonist activities on tissues responsive to oestrogen
What does raloxifene stimulate and inhibit?
stimulates osteoblasts
inhibits osteoclasts
How does raloxifene work as an agonist?
agonist on bone and partially on cholesterol metabolism
- dec in total and LDL cholesterol
How does raloxifene work as an antagonist?
on the hypothalamus or in the uterine or breast tissue
What happens when raloxifene undergoes 1st pass metabolism?
gives glucuronide in the liver
which undergos enterohepatic recycling
What is teriparatide?
a recombinant of human parathyroid hormone
How does teriparatide work?
- stimulates new formation of bone and increases structural integrity and bone strength
- increases the no of osteoblasts and activates the osteoblasts already in the bone
- reduced osteoblast apoptosis
dose of teriparatide
20mcg OD by SC injection (thigh/abdomen)
for 24mths only
teriparatide s/e
nausea oesophageal reflux hypotension dyspnoea depression dizziness
When is teriparatide given?
2nd line for secondary prevention os osteoporotic fragility fractures in pstmenopausal women
- ci/intolerant to alendronate/risedronate
- no response to alendronate/risedronate and over 65yrs AND T score of < -4.0 OR < -3.5 with 2+ fractures OR 55-64yrs and T score < -4.0 with 2+ fractures
treatment duration of teriparatide
max 24 months
course never repeated
What is osteomalacia?
bone condition in which inadequate mineralisaton of bone results from a Ca or P deficiency or both
What is riskets?
disorder of vit D deficiency,
inadequate Ca absorption,
impaired mineralisation of bone in children
What is Paget disease?
progessive skeletal disorder that involves excessive bone destruction and repair
characterised by increasing structural changes of the long bones/spine/pelvis/cranium
drugs to treat Paget disease
bisphosphonates
calcitonin
