AID Flashcards
What hormones are involved in bone health and bone remodelling? (4)
Oestrogen (bone health)
PTH (calc. homeostasis, raises serum calc. in response to falls)
Vit. D (acts in synergy with PTH)
Calcitonin (lowers serum calc.)
What is bone composed of? (3)
Cortical (compact) bone
Trabecular (spongy, cancellous ) bone
Combo of strength + lightweight rigidity
How is cortical + trabecular bone organised? (2)
Cortical = regular structure of osteons Trabecular = strut-like structure
From what lineages are OCs + OBs derived? (2)
OCs = haemopoietic SCs OBs = mesenchymal SCs
What are osteoclasts? (3)
Large multinucleate cells
Secrete acid to dissolve mineral content of bone
And enzymes to degrade the organic matrix
What is the organic matrix (osteoid) mainly composed of? (1)
Collagen type I
What are osteoblasts? (3)
Main cell responsible for forming new bone
Lay down osteoid
And contribute to subsequent mineralisation (giving bone its rigidity)
In general, how are the life cycles of OCs/OBs controlled? (3)
By various local + systemic factors
That promote/inhibit their differentiation
Or promote/delay their apoptosis
What happens to OBs that don’t undergo apoptosis? (1)
They terminally differentiate into osteocytes
What are osteocytes? (5)
Mature bone cells Become entombed in organic matrix May live for decades Important reg/co-ordinating role Sense stress in skeleton + respond to control interplay b/w OCs + OBs
What happens when OBs differentiate into osteocytes? (3)
Become surrounded by bone
With their cell bodies within lacunae (space in matrix)
Give off cellular processes (dendrites) which run along canalculi (tunnels)
What is the function of the Lacunar-Canicular network? (4)
Allows communication b/w osteocytes
And from osteocytes to surface cells/systemic circulation
Responds to both mechanical + systemic/endocrine stimuli
Responsible for porous characteristic + can visualise using dye
What is the function of osteocytes? (2)
Regulate bone modelling in response to mech + endocrine stimuli
Function as endocrine in own right e.g. release FGF23 (which has multiple functions e.g. phosphate metabolism in kidney)
How is remodelling of bone controlled? (3)
By direct interaction b/w OCs + OBs
And via osteocyte network
Anything tipping the balance results in either loss or gain of bone
Which factors favour resorption? (2)
Removal of mechanical loading
E.g. bed rest, zero gravity
Which factors favour formation? (1)
Load-bearing exercise
What are the actions of PTH? (6)
Maintains tight -ve feedback control of serum calc (2.2 - 2.6 mmol L-1)
Responds to decreases in calc + acts to raise serum calc
Stimulates conversion of active hormonal vitamin D (calcitriol)
By stimulating 1- α hydroxylase in kidney
Increase Ca resorption in kidney
Stimulate bone remodelling - both anabolic + catabolic effect = can stimulate/prolong life of both OCs + OBs
What are PTH analogues used to treat? (2)
Diseases of bone loss e.g. osteoporosis
In small, intermittent doses can increase bone mas
What are the actions of vit. D? (3)
Increases Ca2+ absorption from gut
Promotes differentiation of both OC + OB lineages
Can inhibit PTH release by inhibiting 1- α hydroxylase
What are the actions of calcitonin? (4)
-ve feedback regulation of serum calc
Responds to rises in calc + acts to lower calc conc
Inhibits OC function (calcitonin receptors on OCs)
Used to treat diseases of bone loss (but worries over increased risk of malignancy)
What are the actions of oestrogen in bone? (5)
Regulates OB + OC life cycles
Shorten OC life (promote apoptosis)
Lengthen OB life (protect from apoptosis)
Indirectly inhibit osteoclast differentiation through inhibition of cytokine release
(May be necessary for new bone formation in response to mechanical stress - mouse models)
What is RANK? (3)
Receptor activator of nuclear factor kappa-B
Surface receptor on OC precursor cells
That stimulate OC differentiation
What is RANK-L? (3)
Produced by pre-OBs, OBs + osteocytes
Binds to RANK
To stimulate OC differentiation
What is OPG? (4)
Osteoprotogerin
Decoy receptor produced by osteocytes
Bind to RANK-L
Hence preventing activation of RANK
How is the induction of osteoclast differentiation controlled? (1)
Balance of RANK-L + OPG
What is denosumab? (3)
Human monoclonal Ab against RANK-L
Recent treatment for osteoporosis
What is sclerostin? (3)
Protein secreted by osteocytes
Acts as brake on bone formation
Via inhibition of Wnt signalling pathway
What metabolic disease is bone susceptible to? (1)
Conditions such as osteoporosis + osteomalacia
What is osteoporosis? (3)
Loss of bone mass from both cortical (thinning) + trabecular (eating away of) bone
Resulting in weaker, more fracture prone bones
T score of -2.5 or lower
What is osteomalacia? (2)
Loss of bone mineralisation
T score of lower than -1 + greater than -2.5
What are some causes of osteoporosis? (5)
Endocrine disorders Malignancy Drug-induced Renal problems Nutrition i.e. lack of calc/vit. D
What are the endocrine causes of osteoporosis? (3)
Hypogonadism (any cause of oestrogen deficiency) Excess glucocorticoids (exogenous or endogenous) - cortisol has catabolic effects Hyperparathyroidism/hyperthyroidism
What is post-menopausal osteoporosis related to? (1)
Large decline in oestrogen levels
How is osteoporosis diagnosed? (2)
Measure bone mineral density
Using a dual-energy X-ray absorptiometry (DEXA)
What is a T score? (2)
Number of SDs below average for young adult at peak BMD
Used diagnostically for osteoporosis
T score table (4)
Normal = -1 or greater
Osteopenia (bone loss below level of that in osteoporosis) = lower than -1 + greater than -2.5
Osteoporosis = -2.5 or lower
Severe osteoporosis = -2.5 or lower + presence of at least 1 fragility fracture
What is a Z score? (1)
Comparison to the age matched normal of BMD
What happens to bone mass as age increases? (3)
Peak bone mass achieved ~25-30yrs
From 30+ = gradual decline
Menopause causes slight acceleration of decline in women
What are age-related risks of osteoporosis? (2)
Early menopause as decline in bone mass begins earlier + is steeper
Failure to achieve a high peak bone mass when young
What is the most common early manifestation of the menopause? (2)
Vasomotor symptoms (hot flushes) Main driving force for seeking treatment as can be very debilitating
What are the links b/w menopause + osteoporosis? (2)
Later manifestations lead to accelerated bone loss + risk of osteoporosis
~1/3 risk of 50+ woman suffering an osteoporotic fracture (compared to ~1/5 for a 50+ man)
What treatments are there for osteoporosis? (5)
HRT - well established effects, LT treatment is questioned
Bisphosphonates e.g. alendronate - inhibit OC function
PTH analogues
Denosumab - human monoclonal Ab against RANKL
Lifestyle
What lifestyle advice is there for those suffering osteoporosis? (3)
Ensure adequate intake of calc. + vit. D
- but no benefit in suplemmentation if intake is already adequate
Appropriate exercise
What was the WHI RCT on HRT? (4)
2 parallel studies
- progestin + oestrogen in 16k women with womb
- just oest in 10k women who had had a hysterectomy
First trial terminated after 5yrs due to increased breast cancer risk
Second trial terminated after 7yrs due to increased stroke risk
How were the guidelines for HRT modified after the WHI RCT? (3)
ST therapy (3-5yrs) for treating vasomotor symptoms Lowest effective dose to be used LT not recommended
Absolute risk vs relative risk (3)
Media often fails to differentiate b/w the two
Relative risk = how much more/less likely the disease is in one group compared to another
Absolute risk = prob of occurrence of event in a pop relative to its exposure to a specific hazard/pathogen
What were concluded to be increased risks of HRT by WHI study? (3)
Increase risk of stoke
Increased risk of breast cancer
Increased risk of colon cancer
What did further analysis of the WHI HRT study conclude? (2)
WHI participant were older, post-menopausal women - mean age of 64 + 10yrs
Separate analysis of 10yrs post-menopausal suggested risk were reduced in earlier group
What are the 3 major views of why we age? (3)
Wear + tear
Adaptive evolutionary
Non-adaptive evolutionary
What is the wear + tear view of ageing? (5)
View organism as machine that wears out BUT - not all animals age e.g. sea anemone - ability to repair e.g. germ lines - we can repair whole organs e.g. salamander limbs Therefore W+T cannot be whole answer
What is the adaptive evolutionary view of ageing? (3)
Developed through process of evolution + natural selection
Ageing selectively advantageous to species
Prevents old + worn out individuals competing
What are the problems with adaptive evolutionary theory? (3)
Advantage to population not individual
Ageing is rarely seen in natural population
Prevents old and worn out individuals competing (circular argument)
What theories make up non-adaptive evolutionary? (3)
Mutation accumulation
Antagonistic pleiotropic genes
(Disposable soma theory)
What is mutation accumulation? (4)
Powers of natural selection decline with age
Early expressed genes effect most of population
Those expressed after reproduction are lost from evolutionary control
Ageing due to miscellaneous collection of late acting deleterious genes
What experimental support is there for mutation accumulation? (1)
None
