Where does most intracellular calcium exist?
mostly in mitochondria and the ER. Intracellular calcium tends to fluctuate greatly, but always less than 1uM
How does most bone calcium exist?
99% is in mineral phase and the rest is in a pool that can rapidly exchange with extracellular calcium
Where else is calcitonin secreted besides the thyroid C cells?
lung and intestinal tract
How does PTH act at a molecular level?
Binds to a pasma membrane receptor and acts through Gs proteins to inrease cAMP and PKA (thus, urinary cAMP is a test for PTH)
What are the pharm treatments for hypoparathyroidism?
hPTH is available has a short half-life (peptide) so it is more commonly treated with VitD, with or without dietary calcium supplements
What are some hPTH hormones?
Teriparatide (1-34) (forteo)
Full length PTH (1-84)
Describe the uses of Teriparatide?
stimulates bone formation at low doses (important for women with osteoporosis after bisphosphonate therapy). May stimulate IGF-1
What is the use of Raloxifene (Evista)?
A selective estrogen receptor modulator approved for osteoporosis that has beneficial effects of estrogen without stimulating breast cancer
What is Denosumab (Prolifa, Xgeva)?
A monoclonal Ab to RANKL on osteoblasts (60mg dose per 6 month) that blocks stimulation of osteoclast formation for osteoporosis treatment.
Can be used to increase bone mass in pts with breast or prostate cancer
What are the roles of FGF23?
inhibits production of vitD and thus opposes PTH at the kidneys (produced by osteoblasts and osteoclasts)
How does calcitonin work?
binds to plasma membrane receptors and decreases the ruffled border surface area on osteoclasts. Not a global inhibitor of PTH
How is hypercalcemia treated in the short-term?
calcitonin (Calcimar and Miacalcin from salmon (pore potent)) great for short-term (Ab development occurs with long-term use even with hCT)
prednisone can also be used (takes 1-2 weeks) and shouldnt be taken for very long
Other uses of calcitonin?
osteoporosis (injection and nasal spray)
What are the uses of calcitriol in therapeutics?
-prophylaxis and cure of dietary rickets
-treatment of metabolic rickets and osteomalacia
-Tx of hypoparathyroidism
-prevention and Tx of osteoporosis
What is Calcipotriol (an anlog of Calcitriol) used for?
Tx of psoriasis (topical Dovonex)-more effective than glucocorticoids
What are bisphosphonates?
non-hydrolyzable analogs of inorganic pyrophosphate that inhibit bone resorption for treatment of things like Paget's disease and osteoporosis
What are the bisphosphonates used in Paget's Tx?
Etidronate (Didronel),- first gen
alendronate (Fosamax) -second gen, and
risedronate (Actonel)- third gen
What bisphosphonate is used for osteoporosis tx?
T or F. All bisphosphonates are very poorly absorbed from the Gi
T. Must be taken after an overnight with a full glass of water. No food for 30 min
Other second gen bisphosphonates?
alendronate (Fosamax), panidronate (Aredia), and ibandronate (Boniva)
10-100x more potent
Other third gen bisphosphonates?
1000-10000x more potent
risedronate (Actonel) and zoledronate (Zometa)
AEs of bisphosphonates?
-osteonecrosis of the jaw (swelling and loosening of the teeth is often seen). Surgical correction makes elsions worse and 80% of cases follow dental extraction
Much more common with 3rd gen drugs
Osteonecrosis of the jaw
many cases are complicated by infection and occur mainly in pts. with cancer after prolonged therapy
_______ are a common drug cause of osteoporosis in adults
Glucosteroids (by antagonizing Ca uptake in the intestine)
Clinical utility of glucocorticoids?
useful in reversing lymphoma-induced hypercalcemia
What bone issues can estrogen be used to treat? AEs?
effective in preventing osteoporosis (replacement therapy trials do increase risk of thrombosis though especially in women that smoke!!)
Bisphosphonates in metastatic disease treatment
There is evidence to suggest utility of using bisphosphonates as the standard of care for pts. with bone mets from breast and prostate cancer. These pts. receive IV bisphosphonate therapy from the time of diagnosis (most commonly Zometa or Aredia)
The use of bisphosphonates shows a decrease in skeleal complications by up to 1/3rd.
What are calcimimetics?
mimic binding to CaSRs
Cinacalcet (Sensipar) approved for hyperparathyroidism with parathyroid carcinoma
What is Plicamycin (mithracin)?
ABX used for Paget's disease and hypercalcemia for many years (now seldom used)
What is Strontium ranelate?
Drug commonly used to Europe for osteoporosis that blocks differentiation of osteoclasts and promotes apoptosis, while also promoting bone formation and increasing bone mineral density.