Calcium, bone and osteoporosis Flashcards
what do osteoclasts do
dissolve the bone and release IGF1 and TGFβ (transforming growth factor)
what recruits osteoclasts to bone
cytokines (ILs) and parathyroid hormone
what do osteoblasts do
lay down new oesteoid which will then become the new bone matrix
what are osteocytes
bone cells which are osteoblasts that became embedded in the matrix
at what age does bone loss start occuring
age 35-40
what % rate bone loss happens per year in both sexes
0.5-1%
why does bone decrease by 0.5-1% per year in both sexes
due to decrease in osteoblast numbers
what is the rate of loss increase during menopause in women
10X increase
why does bone decrease by 10X during menopause in women
due to increase in osteoclast activities
what % of the body calcium is contained in bone
98%
what % of the body phosphates is contained in bone
85%
how is calcium phosphate stores as in bone (name and formula)
hydroxyapatite, Ca10(PO4)6(OH)2
what is the formula for hydroxyapatite
Ca10(PO4)6(OH)2
what are the 3 major hormones involved in bone metabolism and remodeling
parathyroid hormone, vitamind D, calcitonin
what does high plasma [Ca++] do to PTH release
decreases PTH release
what does low plasma [Ca++] do to PTH release
increases PTH release
what G proteins are coupled to Ca++ sensing receptors
Gq Gi
what does high [PO4-] do to PTH secretion and how
indirectly increases
-forms complex with Ca++, so less Ca++ in plasma
what does low [PO4-] do to PTH secretion and how
indirectly decreases
-forms complex with Ca++, so more Ca++ in plasma
what does calcitriol do to PTH release and why
makes less, suppresses PTH gene expression
what is calcitriol
a vitamin D metabolite
what does high intracellular Ca++ do to PTH secretion
inhibit
because that means Gq was activated by Ca++ in plasma and high plasma Ca++ means low PTH
what does low intracellular cAMP do to PTH secretion
inhibit
because that means Gi was activated by Ca++ in plasma and high plasma Ca++ means low PTH
what does PTH do to the bone
induce osteoblasts to express and secrete a protein RANKL (RANK ligand)
what are PTH receptors coupled to
adenylate cyclase
what does RANKL do
activate RANK receptors on osteoclast precursors to cause differentiation and activation of osteoclasts
what does RANK receptor activation on osteoclasts do
cause differentiation and activation of osteoclasts
what bone cell has RANK receptors
osteoclasts
which bone cell releases RANKL
osteoblasts
what does an increase in bone resorption lead to
bone formation
what does intermittent exposure to PTH promote
bone formation
what does chronic high level exposure to PTH promote
bone resorption
what does PTH do to GI tract
increase in Ca++ and phosphate absorption via an increase in synthesis of calcitrol in the kidney
what does PTH do to Ca++ absorption
increase
what does PTH do to phosphate absorption
increase
what does PTH do to calcitriol synthesis (where does this occur)
increase, in the kidney
where does calcitriol synthesis occur
in the kidney
what does PTH do to kidney
- increase calcitrol synthesis
- increase Ca++ reabsorption
- increase PO4- excretion
what do kidneys do to Ca++ reabsorption (with PTH)
increase
what do kidneys do to phosphate excretion and how (with PTH)
increase excretion by decreasing reabsorption in proximal tubules
what does PTH do to plasma calcium
elevates
what does PTH do to plasma po4-
decrease
what is a synthetic PTH used for in osteoporosis
PTH 1-34
what are the 2 major sources of vitamin D called
ergocalciferol (D2)
cholecalciferol (D3)
where does ergocalciferol (D2) come from
plants
where does cholecalciferol (D3) come from
in the skin, generated by UV light
is D2 or D3 more strong in humans
same potency
what is vitamin D tho and what does it do
a prohormone that is converted into a number of biologically active metabolites
what enzyme converts calfidediol into calcitriol
25(OH)D1αhydroxylase
where is calcifediol produced
in the liver
where is calcitriol produced
in the kidney
what does calcitrol do to PTH production
inhibit
what does high calcitrol do to PTH production
inhibit
what does low calcitrol do to PTH production
enhance
what does calcitrol do to calcitrol production
inhibit
what is calceifediol
the main storage form of vitamin D
what does calcifediol do to Ca++ (renal)
stimulates renal reabsorption
what does calcifediol do to PO4-
stimulates renal reabsorption
what does calcifediol do to Ca++ (muscle)
regulates Ca++ inlfux and contractility
where is excessive vitamine D stored
in body fat
what does vitamin D binding protein have high affinity to
calcifediol
what does vitamin D binding protein have low affinity to
calcitriol
what is the most potent vitamin D metabolite
calcitriol
what is the vitamin D metabolite with the longer plasma half life
calcifediol (23 days) vs calcitriol (hours)
what is calcitriols affinity to vitamin D binding protein
low
what is calcifediol affinity to vitamin D binding protein
high
what does calcitriol do to osteoblasts and what does this cause
induces RANKL secretion from osteoblasts so more recruitment of osteoclast precursor cells and maturation of osteoclasts
this causes production of osteocalcin
what does calcitriol do to bone (major effect)
bone resorption
what is osteocalcin
Ca++ binding protein in bOne maTriX
what secretes osteocalcin
osteoblasts
why do osteoblasts secrete osteocalcin
to regulate bone mineralization
what does calcitriol do to GI tract
increased Ca++ and PO4- absorption
what does calcitriol do to Ca++ reabsorption
increase absorption
what does calcitriol do to PO4- absorption
increase absorption
how does calcitriol increase Ca++ absorption in GI (3)
by increasing Ca++ binding proteins. TPV6 Ca++ channels and Ca++ flux across basal lateral membranes
what does calcitriol do to plasma Ca++
increase
what does calcitriol do to plasma PO4-
increase
what does calcitriol do to kidney
decrease ca po4 excretion
what does calcitriol do to ca in kidney
decrease excretion
what does calcitriol do to po4 in kidney
decrease excretion
what does calcitriol do to parathyroid glands
decrease PTH secretion
what does calcitriol do to PTH secretion
decrease
what does calcitriol do to other tissues
cell maturation and differentiation
what are 4 common therapeutic uses for vitamin D
- hypocalcemia
- rickets
- osteomalacia
- osteoporosis
what is hypocalcemia
failure to mineralize newly formed bone in children, resulting in bone softening and skeletal deformities
what is osteomalacia
accumulation of undermineralized bone matrix in adults, associated with bone pain and tenderness
what are 5 possible causes of hypocalcemia
hypoparathyroidism vitamin D deficiency chronic kidney disease malabsorption (GI disease) liver disease
why would chronic kidney disease cause hypocalcemia
decrease in calcitriol synthesis
why would liver disease cause hypocalcemia
decrease in calcifediol formation
what are 4 manifestations of hypocalcemia
tetany (tremor/spasms), paresthesia, muscle cramps, seizures
what is the main treatment for hypocalcemia
Ca++ supplement in conjunction with calcitriol
why is Ca++ supplement given in conjunction with calcitriol
cause calcitriol helps it absorb in the GI
what can cause rickets and osteomalacia (4)
nutritional
hypophosphatemic vitamin D resistant
type 1 vitamin D dependent (pseudovitamin D deficiency)
type 2 vitamin D dependent (hereditary vitamine D resistant)
how can you fix nutritional causing rickets and osteomalacia
cod liver oil or vit D supplement
what is hypophosphatemic vitamin D resistant
genetic disorder resulting in reduction in renal PO4- reabsorption and decrease calcitriol production
what is phosphate critical for with bones
BONE mineralization
how do you treat hypophosphatemic vitamin D resistant
calcitriol and phosphate supplement
what causes type 1 vitamin D dependent (pseudovitamin D deficiency)
mutation in 25(OH)D 1 hydroxylase
what are you deficient in with type 1 vitamin D dependent (pseudovitamin D
calcitriol production
how do you treat type 1 vitamin D dependent (pseudovitamin D
calcitriol
what causes type 2 vitamin D dependent (hereditary vitamin D resistant)
mutations in the gene for vitamin D receptors
what is serum cortisol levels in type 2 vitamin D dependent (hereditary vitamin D resistant)
actually high (but low tissue response)
how do you treat type 2 vitamin D dependent (hereditary vitamin D resistant)
high dose of calcitriol
kind of cell releases calcitonin
parafollicular C cell in thyroid gland
what triggers calcitonin release from parafollicular C cell in thyroid gland
high Ca++ in plasma
which G receptors is calcitonin coupled to
Gs
what does calcitonin do to bone
less osteoclast activities
less bone resorption
how do the bone effects of vitamin D and calcitonin compare
they are opposite
what does calcitonin do to GI
increase Na+ K+ Cl- H2O secretion
less gastrin and gastric acid secretion
what does calcitonin do to kidney
less Ca++ and PO4- reabsorption
and other ions (Na+ K+Mg++)
what does calcitonin do to plasma Ca++ levels
lower
what does calcitonin do to plasma PO4- levels
lower
is calcitonin used for osteoporosis and why
no cause it gave tumors
what does hypercalcemia manefest as
CNS depression
coma
fatigue
muscle weakness
what can cause hypercalcemia
cancer that stimulates bone resoprtion, hyperparathyroidism
what is pagets disease
abnormality in bone remodelling: uncontrolled osteoclastic bone resorption, secondary increases in poorly organized bone formation
what causes pagets disease
unknown, maybe virus
how can you treat pagets disease
calcitonin
how can calcitonin help pagets disease
lowers pain and compilation
what is osteoperosi (simple)
increase in bone resorption relative to bone formation
what are 2 common causes of osteoporosis
low sex hormone production
low vitamin D level and GI Ca++ absorption
what are 4 less common causes of osteoporosis
glucocorticoids
thyrotoxicosis (thyroid hormone stimulates osteoclasts)
hyperparathyroidism
alcohol abuse (decrease vit D uptake)
what are 6 treatments for osteoporosis
teriparatide (fragment of PTH) vit D supplement Ca++ supplement biphosphonate estrogen replacement therapy/ receptor modulators denosumab
how many generations of biphosphonates have there been
3
how do 1st gen biphosphonates work
metabolize into a nonhydrolyzable ATP analog that accumulates within osteoclasts and induce apoptosis
what happens if given a 1st gen biphosphonate at continuously at high doses
osteomalacia (bone minerilzation, softening)
are 1st gen biphosphonates given as a first line of treatment
no
how do 2nd gen biphosphonates work
inhibit farnesyl pyrophosphate synthesis, an enzyme that is important for osteoclast function and survival
how must 2nd gen biphosphonates be administered
first thing in the morning on an empty stomach
how much more potent are 2nd gen biphosphonates than 1st gen
10-100
how do 3rd gen biphosphonates work
inhibit farnesyl pyrophosphate synthesis, an enzyme that is important for osteoclast function and survival
how much more potent are 3rd gen biphosphonates than 1st gen
10 000
how can you administer 3rd gen biphosphonates
once a year IV
what do biphosphonates do to bone remodeling and how
decrease by decreasing osteoclast activity
what do biphosphonates do to osteoclast activity
reduce
where is the action of biphosphonates concentrated
at the site of active bone remodeling
what do biphosphonates do to hydroxyapatite
reduce formation and dissolution of hydroxyapatite
what are 4 therapeutic uses of biphosphonates
pagets disease
prophylaxis + treatment of osteoperosis
hypercalcemia
prevent fracture in patients with bone metastases
what is a complication with using biphosphonates
osteonecrosis of jaw (more with 3rd gen due to limit of blood supply)
what happens to calcium levels in blood when on biphosphonates and why
lowers because they inhibit bone resorption
how is estrogen good for osteoperosis
it opposes the action of PTH on bone resorption
how does estrogen oppose the action of PTH on bone resorption
there are estrogen receptors on bone
is estrogen used in postmenopausal women for osteoporosis and why
no because there is an increase risk in breast cancer with long-term use
what do SERMs stand for
selective estrogen receptor modulators
what do SERMs do to bone
agonist effects on bone - behaves like estrogen
what do SERMs do to lipid metabolism
agonist effects on lipid metabolism - behaves like estrogen
what do SERMs do to breast tissue
antagonist effects on breast cancer - so wont cause cancer
what do SERMs do to uterus
its inactive
when are SERMs used
alternative to estrogen replacement therapy
what do SERMs do to thromboembolic events
increased risk
what are the agonist effects of SERMs
on bone and lipid metabolism
what are the antagonist effects of SERMs
on breast tissue
what is denosumab
a human monoclonal antibody
what does denosumab do/cause
reduces the stimulatory action of RANKL on osteoclasts formation and activation
what is the mechanism of denosumab
binds to RANKL to prevent it from binding to RANL receptors on osteoclast precursor cells (so it wont become an osteoclast)
which drug can be used for postmenopausal osteoporosis
denosumab
can denosumab be used for postmenopausal osteoporosis
yes
what do glucocorticoids do to bone (2)
decrease bone formation
decrease activities of osteoblasts
what do glucocorticoids do to bone formation
decrease
what do glucocorticoids do to osteoblasts
decrease activity
what do glucocorticoids do to GI tract
decrease Ca++ and PO4- absorption
what do glucocorticoids do to Ca++ absorption
decrease
what do glucocorticoids do to PO4- absorption
decrease
what do glucocorticoids do to kidneys
increase Ca++ excretion
what do glucocorticoids do to Ca++ excretion
increase
what are 3 things that glucocorticoids in treatment of hypercalcemia are good for / associated with
- vitamin D intoxication
- sarcoidosis
- cancers that stimulate osteoclastic bone resorption
what is sarcoidosis
lung granuloma that causes unregulated ectopic production of vitamin D