Bone Metabolisma and Osteoporosis Flashcards
What are the 2 most important mineral for cellular function and where are they mostly found?
calcium (98%) and phosphate (85%) are in bone
Where is there a dynamic exchange between bone and mineral?
in the extracellular fluid
Bone serves as the primary structural framework for the body and provides a space for (blank)
hematopoiesis
What are the three abnormalities that occur with problems of bone metabolism?
cellular dysfunction
defects in structural support
loss of hematopoietic activity
What is an example of cellular dysfunction due to messed up bone mineral metabolism?
muscle weakness, coma and tetany
What is an example of a structural support defect due to messed up bone mineral metabolism?
osteoporosis
What i an example of a loss of hematopoietic activity due to messed up bone mineral metabolism?
infantile osteopetrosis
Tell me about how calcium is regulated
decreased calcium -> Increased PTH-> increased calcium in the blood
Calcitonin reduces plasma calcium levels
What are the three hormones that serve as the principal regulators of calcium and phosphate homeostasis?
PTH, fibroblast growth factor 23 (FGF23), and vitamin D.
What are the stimulators and inhibitors of osteoblast differentiation?
RANKL (+)
M-CSF (+) (macrophage colony stimulating factor i.e. create osteoclasts)
OPG (-) (osteoprogenin)
Explain what RANK and RANKL do?
RANKL (receptor activator ligand) is released by an osteoblast and binds to a RANK (receptor) on an osteoblast precursor to create an osteoclast.
What does OPG do?
it deactivates RANKL to prevent osteoblast differentiation
Describe PTH (structurally)
84 AA, peptide, made in parathyroid glands
What part of the PTH peptide is active?
1-34
How do you regulate PTH?
1) via calcium sensitive protease (limits production)
2) calcium sensing receptor in parathyroid gland reduces PTH production
3) Parathyroid gland has Vit D receptor and CYP27B1 to promote Vit D and suppress PTH
What does PTH do exactly?
mobilizes bone calcium decreases renal excretion of calcium stimulated Vit D synthesis promotes phosphate excretion (i.e wants calcium to be in the blood and wants to get rid of phosphate)
If you have osteoporosis would you want to utilize PTH or vitD3 and calcium?
you can use both but vitD3 and calcium together would be way better
So explain Vit D biosynthesis?
you have 7-DHC in skin gets exposed to UV changes to D3 and goes to liver, liver changes it to 25D3 and gives it to kidney, kidney converts to 1,25 OH D3 to make calcitriol
What is secalciferol?
it is a second pathway that 25 OHD3 can go in the kidney. If you have excess 25 OH D3 or you dont need anymore calcitriol then you will make this instead of calcitriol
What organs are important for calcitriol formation?
skin, liver, kidney
What hormone increases 25OHD3 (calcifediol, i.e the substance that is in kidney waiting to be converted to 1,25 D3) conversion to calcitriol?
PTH :)
How does vit D circulate in the blood?
bound to vit D binding protein
How is vit D cleared from the blood?
rapidly in the liver
What does vit D do?
stimulates absorption of calcium and phosphate in the intestines and mobilization of calcium from bone.
When would you clinically administer Vit D?
osteomalacia (reduced vit D)
hypocalcemia
hypoparathryroidism
What is FGF23 (fibroblast growth factor 23)?
it is a protein (251 AAs) that inhibits 1,25 OH2D production and phosphate reabsorption in the kidney
(i.e inhibits vit D formation)
Where does FGF23 come from?
produced by osteoblast and osteocytes in bone
What inhibits FGF23?
What happens if you have a mutation in this?
DMP1
increased FGF23 and osteomalacia (reduced vit D)
What does FGF23 do?
it keeps vit d from stealing its calcium :)
How do you inactivate FGF23?
What happens if you have a mutation in this resulting in excess FGF23?
via cleavage at an RXXR site
You will get hypophosatemic rickets (osteomalacia)!
How do you stimulate FGF23 production?
Calcitriol, fo real
How does PTH affect the intestine, kidney, bone, and net serum levels?
intestine-> makes calcitriol which stimulates increased Calcium and phosphate
kidney-> decreased calcium excretion, increased phosphate excretion
Bone-> Increased calcium and phosphate resorption (in high doses), increase bone formation (low doses)
Net effect: serum calcium increased, serum phosphate decreased
How does Vit D affect the intestine, kidney, bone, and net effect on serum?
Intestine-> increased calcium and phosphate absorption
Kidney-> reduced calcium and phosphate excretion
Bone-> increased calcium and phosphate resorption via calcitriol, and increased bone formation via calcitriol and secalciferol. i.e. in high calcium concentrations you will increase bone formation, in low concentrations you get bone resorption)
Serum-> calcium and phosphate increase
How does FGF23 affect the intestine, kidney, bone and net effect on serum?
(remember this inhibits Vit D)
Intestine-> decreased calcium and phosphate absorption by decreasing vit D production
Kidney-> increased phosphate excretion
Bone-> decreased mineralization (due to low vit D)
Serum levels-> decreased serum phosphate
How do you regulate PTH, FGF23 and vit D?
Are these major contributors to bone mineral homeostasis?
via secondary regulators
no, their impact is minor however they can be exploited for therapeutic use
What is a protein hormone made up of 32 AA produced by the thyroid gland?
calcitonin
What all does calcitonin do?
inhibits osteoclasts
decreases reabsorption of calcium and phosphate in proximal tubule of kindey
(i.e lower plasma calcium concentrations)
Where does calcitonin inhibit calcium and phosphate reabsorption?
in the proximal tubule of the kidney
What prevents vit D from working its magic on the intestine so you get increased renal excretion of calcium and inhibition of bone formation?
glucocorticoids
Pharmacologically, how can glucocorticoids be used?
to reverse hypercalcemia (ass. w/ lymphomas and granulomatous diseases, sarcodosis) in which Vit D is elevated
Prolonged use of (blank) is a common cause of osteoporesis in adults an stunted skeletal development in children.
glucocorticoids
i.e steroid induced osteoporosis
An estimated 10-20% of a women’s bone mass is (blank) dependent
estrogen
How does estrogen help with osteoporosis?
estrogen inhibits osteoclast activity. So if you have a menopausal women she will have reduced estrogen-> increased osteoclast activity-> brittle bones
(blank) acts to reduce the bone-resorbing actions of PTH
estrogen
What does estrogen increase the blood levels of?
increases calcitrol but has not direct effect on its production.
Increased 1,25 OH2D as a result of estrogen treatment decreases what?
serum calcium and phosphate
Does estrogen have direct or indirect effect on bone remodeling?
direct, in fact their are calcium receptors in bone :)
(blank) is characterized by a reduce quantity of bone
osteoporosis
(blank) is characterized by a lack of mineralization
osteomalacia (like rickets, lack of vit D, decreased phosphate and calcium)
(blank) is characterized by the production of abnormal bone
pagets disease (abnormal break down and weird build up of bone)
What am I talking about:
affects 3% of pop. over age of 60
disease of bone, present with bone pain, skeletal deformity, neurological complications or fractures
common in white countries (except for scandinavia)
excessive bone resorption and formation in 3 phases
Pagets diseae
What are the 3 phases of bone formation in Paget’s disease?
osteolytic
osteoblastic
quiescent
(all 3 phases may be present in the same patient at the same time)
What am I talking about:
caused by decreased mineralization of new bone matrix
in children lack of calcification results in growth failure and rickets
adults present with bone pain, proximal myopathy or fractures with minor trauma
Caused by vit D deficiency
Osteomalacia
If you were trying to figure out if someone had osteomalacia, what would their labs look like?
low vit D
hypocalcemia
increased PTH (secondary)
What are the cause for osteomalacia (more specific than vit D deficiency)?
Insufficient Exposure to sunlight, Malnutrition; Renal tubular acidosis; Malnutrition during pregnancy; Malabsorption syndrome; Hypophosphatemia; Chronic renal failure; Tumor induced ostemalacia; Long term anti-convulsive therapy; Coelaic disease; Cadmium poisoning
What am I talking about:
common in postmenopausal women
-> common to get hip, forearm, and spinal fractures
increased morbidity and mortality
accelerated by premature or surgical loss of ovarian fnction, drugs, lifestyle
osteoporosis
What are risk factors for osteoporosis?
old, white/asian, females, who are short and skinny and sit around all day drinking and smoking and hate eating calcium who go into menopause early
During what years does bone formation increase?
birth to 30 years (then slowly declines; occurs more rapidly in early postemenpausal years)
Bone formation and resorption can be semi-quantified on (blank or blank)
bone biopsy or radiographic imaging
What is the most common problem associated with women with osteoporosis?
How about women without osteoporosis?
fractures
stroke
What happens if you are older and have a fracture?
your more likely to die :(
What is recommended for women age 65 or older OR for woman at risk of osteoporosis?
DEXA/DXA test (bone density test)
What will the DXA test give you and tell you?
it will give you a T-score
above 1=normal bone
b/w -1 to -2.5 = signs of osteopenia (below normal bone density but not quite osteoporosis)
below -2.5= osteoporosis
What is HRT used for?
estrogen inhibits osteoclasts so you get increased bone density YAY!
(helps with symptoms of menopause)
What are the three favorite oral estrogens that are taken for HRT?
equine estrogen, estrone sulfate, and miconized estradiol
When can you take progesterone rather than estrogen?
as long as you dont have a hysterectomy
What is worrisome about HRT and when should you prescribe them?
shown to cause CV problems, dementia, and ovarian/breast cancer
To treat symptoms of menopause (vaginal bleeding or dryness, hot flashes, mood changes and osteoporosis)
For short period of time*
After a hysterectomy, estrogen only hormone therapy does not increase a woman’s risk of (blank)
breast cancer
What are SERM drugs?
selective estrogen receptor modulators-> have tissue specific effects
They competively bind estrogen receptors and induce effects
What happens when a SERM drug binds to an alpha estrogen receptor?
They act as competitive inhibitors
What happens when a SERM drug binds to a beta estrogen receptor?
Have agonist effects
What are 2 SERMS that protect against osteoporosis?
Tamoxifen and Raloxifene
What blocks estrogen receptors in breast cancer cells who growth is estrogen dependent?
tamoxifen :))))))))
How should you prescribe tamoxifen for someone with breast cancer?
in conjuction with surgical or chemotherapeutic options
Should you give tamoxifen to someone how doesnt have breast cancer but is at risk?
Yes :)
Since tamoxifen blocks estrogen receptors, what will happen to estrogen levels in the body?
surprisingly nothing will really happen, your lipid profile will remain fine and osteoporosis will not be accelerated
What is a negative about tamoxifen?
it leads to increased risk of endometrial cancer
AND
can give you hot flashes, nausea or vomiting :(
So how can tamoxifen treat osteoporosis but then also be used to inhibit estrogen receptors for breast cancer?
well tamoxifen is amazing and works as both an antagonist and an agonist so in breast cancer it works as an antagonist YAY and for osteoporosis it works as an agonist to inhibit osteoclasts YAY
Why is raloxifene amazing!
it has estrogenic activity, helps with osteoporosis (acts as an agonist), decreases cancer by 50% (acts as an antagonist) AND decreases cholesterol.
What are some adverse effects of raloxifene?
increased thrombi
hot flashes
leg cramps
What are bisphosphonates?
Enzyme resistant analogs of pyrophosphate
What do bisphosphonates do?
reduce bone turnover
reduce formation, aggregation and dissolution of hydroxyapatite crystals in bone
How do bisphosphonates reduce bone turn over?
they mimic pyrophosphate and prevent number and activity of osteoclasts after 48 hours
Bisphosphonates inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis, or cell death, thereby slowing bone loss.
How do bisphosphonates reduce formation, aggregation and dissolution of hydroxyapatite crystals in bone?
by blocking transformation of calcium phosphate into hydroxyapatite
What are three important bisphosphonates?
etidronate
alendronate
risedronate
What does etidronate do and how should it be given?
it increased bone density
intermittently as to prevent osteomalacia
What does alendronate do?
it increased bone density and reduces fractures significantly single vertebral (50%) multiple vertebral (90%)
Should bisphosphates be taken with milk products, food or calcium supplements?
no because these will inhibit the drugs absorption
instead drink water and dont lay supine
What are the adverse effects of bisphosphonates?
GI, ulcers, osephagitis
What is this:
Human monoclonal antibody against RANKL (converts osteoblasts to osteoclasts) and is used for the treatment of osteoporosis, treatment of bone loss and bone metastasis, rhuematoid arthritis, multiple myeloma and giant cell tumor of the bone
Denosumab
(blank) inhibit the maturation of pre-osteoclasts into osteoclasts and therefore prevents bone resorption. It mimics the actions of osteoprogenin, an endogenous RANKL inhibitor that is decreased in patients with osteoporosis.
Denosumab
How effective is denosumab? What are its issues?
decreased fractures of 60-90 year olds by 35%
increased urinary and respiratory infections, rashes, joint pain, eczema
When cant you give someone denosumab?
when they are hypocalcemic
Does calcium help with osteoporosis?
yeah kind of, when coupled with Vit D it definitly helps
(blank) is a synthetic C-19 steroid with weak hormonal properties. Short term studies have shown increases in bone mass in the spine and prevention of bone loss from the forearm in postmenopausal women
tibolone
(blank) is a PTH analog used in cyclic doses and has been shown to be effective in the treatment of osteoporosis
teriparatide
What is the most effective treatment for osteoporosis but can only be used for a short amount of time?
teriparatide
What is very effective for treatment of osteoporosis and can be used for a long time?
PTH and estrogen
Since hypercalcemia is life threatening, how do you deal with this?
give fluid resuscitation and loop diuretics that augement renal Ca2+ excretion
What else other than fluid resuscitation can hep with hypercalcemia?
calcitonin (rapid and transient response)
Intravenous bisphosphates (keep calcium levels low)
cinacalcet
What is cinacalcet?
calcium senor mimetic that inhibits PTH secretion
When do you use cinacalcet?
secondary hypercalcemia ass. with parathyroid cancer
OR
secondary hyperparathyroidism due to chronic kidney disease
