Pharmacology of Parathyroids and Bone Flashcards
What type of bone is in the shafts of long bones? vertebral bodies, ribs, pelvis and ends of long bones?
- shafts-cortical
- vertebral bodies, ribs, pelvis and ends of long bones-trabecular
What are the 3 main cell types in bone and what is their function?
- osteoblasts-bone forming cells
- osteoclasts-bon resorption
- osteocytes-communication and mobilization
What are the 2 types of matrix in bone and what are they made up of?
organic-type 1 collagen and proteins
inorganic-hydroxyapatite
What controls the secretion of PTH?
-ionized calcium (when low PTH is stimulated)
Which 2 organs does PTH directly effect?
- bone-releases Ca from bone (activates osteoblasts which activate osteoclasts–>according to pathoma)
- Kidney-reabsorbtion of Ca and production of Vitamin D which leads to absorbtion of Ca and PO4 in small intestine
- All lead to increased serum Ca levels*
What are the 3 forms of Ca in the circulation and which are the most important physiologically?
1) Ionized Ca
2) protein bound Ca
3) Complexed to bicarb, citrate or phos
* *Ionized and free more important physiologically**
Changes in which protein in the blood can affect the measurement of calcium?
albumin
What is the equation to correct Ca based on albumin levels?
corrected Ca= measured Ca+.8 X (4-measured albumin)
What 3 things can increase PT reabsorbtion of Phosphorous?
- phosphate depletion
- hypoparathyroidism
- hypocalcemia
What increased Phosphate excretion?
- PTH
- PTHrp
- hypercalcemia
- hypokalemia
- hypomagnesemia
- calcitonin
- glucocorticoids
- diuretics
What is magnesium necessary for?
the release of PTH and the action of PTH on its target tissues
Where is Vitamin D made? Where do it’s 2 hydroxylations occur? How does it maintain normal serum Ca level?
- made in the skin
- hydroxylations in the liver and kidney
- mantains Ca by increasing absorption of dietary Ca and stimulating bone cells to become osteoclasts
If a patient has hypercalcemia and their PTH level is not suppressed (high or normal) what do they most likely have?
primary hyperparathyroidism-excessive secretion of PTH from parathyroid glands (usually in 6th decade of life)
If a patient has hypercalcemia and their PTH level is low, what other tests should be ordered in order to make a dx?
-PTHrp, Vitamin D, and 24 hour urine calcium
What would the lab values of Ca, PTH, Phosphorous and Urine calcium be like in primary hyperparathyroidism?
- Ca high
- PTH high or normal
- Phosphorous low
- Urine calcium high
What are some of symptoms of primary hyperparathyroidism?
lethargy drowsiness stupor coma proximal muscle weakness hyporeflexia N/V pancreatitis Polyuria Polydipsia Nephrocalcinosis Nephrolithiasis HTN Short QT bradycardia increased sensitivity to digitalis
How is primary hyperparathyroidism usually treated?
Surgery to remove abnormal tissue
if disease is mild or asymptomatic they could be followed
What medications can be used to medically treat hyperparathyroidism?
- Bisphosphonates-tx low bone density
- Calcimimetics: to reduce PTH and Ca levels by altering fxn of Ca sensing receptor
- Sensipar (Cinacalcet): for hyperparathyroidism in renal disease and parathyroid carcinoma or in pts who refuse surgery
What are some other causes of hypercalcemia aside from hyperparathyroidism?
- malignancy
- Familial hypocalciuric hypercalcemia-PTH is normal or slightly high
- milk alkali syndrome-excessive OTC Ca use
- Granulomatous Diseases-can increase Vit D levels
- Medications: thiazides and Lithium
What are the 3 general ways to decrease serum Ca?
- expand volume
- increase urine Ca excretion
- inhibit bone resorption
How is mild hypercalcemia treated? (Ca<12)
increase fluid intake
moderate Ca in diet
avoid certain meds
What are the 5 main treatments for hypercalcemia?
- fluids-possible need for loop diuretic after to increase Ca excretion and prevent volume overload
- Bisphosphonates
- calcitonin
- corticosteroids
- Dialysis
What is the mechanism of Biphosphonates and what are the 2 most commonly used?
- inhibits bone resorption
- Pamidronate and Zoledronic Acid
- Not effective immediately*
What is mechanism of calcitonin and what can repeated exposure lead to, making it most useful in the acute setting?
- rapid lowering of Ca by increasing urinary Ca excretion and inhibiting bone resorption
- repeated exposure can lead to downreg of calcitonin receptors–>tachyphylaxis in 2-3 days
- *lowers Ca 1-2mg/dl within 2-4 hours–>Thus used for SEVERE Hypercalcemia**
What is the mechanism of corticosteroids in the treatment of hypercalcemia?
- decreases production of Vitamin D
* *Used in Vit D intoxication, granulomatous diseases and hematologic malignancies**
When is dialysis used for treatment of Hypercalcemia?
-in pts with renal failure or when there is no response to other treatments
What is secondary hyperparathyroidism? What is the mechanism of this in renal disease?
-PTH secreted in response to perceived low Ca
(Ca is actually low or normal)
-Renal disease- from phosphate retention and deficient Vit D
Phosphate directly stimulates PTH secretion at high levels
How is secondary hyperparathyroidism from renal disease treated?
- low phosphate diet
- phosphate binders
- replacement of Vitamin D
- Calcimimetics
- Dialysis
What is tertiary hyperparathyroidism?
- parathyroid glands become autonomous after prolonged secondary hyperparathyroidism
- *Serum Ca is elevated**
What causes hypocalcemia?
- destruction or failure of parathyroid glands
- inactivity of PTH at target tissues
What are some symptoms of hypocalcemia?
paresthesias bronchospasm laryngospasm tetany seizures increased ICP with papilledema Prolonged QT Heart block CHF Cataracts
What else should be checked when a low serum Ca is obtained?
ALBUMIN!!
could also check Mg, phosphorous and creatinine levels
What do the lab values of Ca, Phosphorous, PTH and Creatinine look like in Secondary hyperparathyroidism due to chronic renal failure?
- Ca-low
- Phosphorous-high
- PTH-high
- Creatinine-high
How does the low excretion of phosphorous and low Vit D in Secondary hyperparathyroidism due to chronic renal failure lead to hypocalcemia?
- decreased Ca absorption from the gut
- decreased Ca mobilization from the bone–>PTH secretion
What are the 3 phosphate binders used to treat Secondary hyperparathyroidism due to chronic renal failure?
- calcium carbonate
- calcium acetate
- sevelamer (renagel)
What are the 2 Vitamin D analogs used to treat Secondary hyperparathyroidism due to chronic renal failure?
- calcitriol
- doxercalciferol
What is hypoparathyroidism?
PTH produced is insufficient to maintain serum Ca levels or unable to fxn at target tissues
What would the Ca, phophorous and PTH levels be like in hypoparathryoidism? What is different in pseudohypoparathyroidism?
- Ca low
- Phosphorous high
- PTH low
- *In pseudohypoparathyroidism PTH is high**
How is hypoparathyroidism treated?
- Oral Ca and Vitamin D
- normalize Ca and Phosphorous levels without causing hypercalciuria
- *Phosphate restricted diet w/ Ca goals on low end of normal**
How might Vitamin D deficiency present?
- low Ca and Phosphorous
- high PTH
- low urine Ca
Which form of Vitamin D is more efficacious; cholecalciferol or ergocalciferol?
cholecalciferol
How is acute hypocalcemia treated?
- tx depends on severity
- Ca gluconate diluted in D5W or NS IV
- Possibly add oral Vitamin D
- If hypocalcemia is persistent tx with supplemental Ca every 6-12 hours
What are some causes of hypophosphatemia?
- decreased intestinal absorption-Vitamin D important for promoting this!!
- increased urinary losses
- transcellular shift
- *lack of VitD may result in rickets or osteomalacia**
How are X-Linked and AD hypophosphatemic rickets characterized?
low phosphorous-decreased reabsorption from renal tubule
- decreased absorption of Ca and phosphorous from intestines
- Varying degree of bone involvement
How is hypophosphatemia treated?
- replacing phosphorous
- calcitriol
What is osteoporosis? How is more susceptible?
- low bone mass, increase in bone fragility
- Women are more susceptible postmenopausal
- Men more likely to have secondary underlying cause
Why does bone loss occur in the post menopausal state?
- increase in rate of bone remodeling
- imbalance in the activity of osteoblasts and osteoclasts
What is a normal T score?
greater than -1
-1 to -2=osteopenia, less than -2.5= osteoporosis
What is the mechanism of bisphosphonates and which ones are currently approved for osteoporosis treatment?
- reduce osteoclast bone resorption and increase BMD, decreased fracture risk
- Alendronate, risedronate, and ibandronate
What are the restrictions when taking bisphosphonates?
Need to be taken:
- fasting
- in the morning
- with full glass of water
- remain upright for atleast 30 mins
- no eating or taking other meds during that time
- *Side effects-local GI irritation**
If the Gi side effects are too much for a pt with osteoporosis what can be done?
Zoledronate-IV once a year
Boniva IV every 3 months
What is the mechanism of action of SERM’s in the treatment of osteoporosis?
- used in postmenopausal women
- estrogen like compounds that decrease bone resorption (selective to bone)
What are the 3 SERM’s?
Raloxifene (risk of DVT and hot flashes)
basedoxifene
lasofoxifene
Where is Calcitonin usually secreted from and what does it do?
- secreted by C-cells in thyroid
- inhibits osteoclast resorption
- *nasal preparation (salmon calcitronin) used in osteoporosis, can cause rhinitis**
What is one unique effect of salmon calcitronin?
has an analgesic effect on acute vertebral fractures
What is Teriparatide and what pts is it reserved for?
- PTH analog
- pts at high risk of fracture or who couldn’t tolerate or have failed other therapies
What are some side effects of Teriparatide and what is it’s black box warning?
SE-dizziness, palpitations, transient hypercalcemia
BB-osteosarcoma in rats
What is Denosumab and what are some possible side effects?
- RANK Ligand inhibitor-antiresorptive (SQ injection every 6 months)
- SE-skin infections, hypocalcemia-especially in those with low GFR
What are some possible future treatments for osteoporosis?
- other anabolic agents
- Cathepsin K inhibitors
- Sclerostin pathway
What is Paget’s disease of bone?
-localized disorder of bone remodeling-from increase in osteoclast mediated bone resorption—>disorganixed bone at 1+ sites
What are some typical sites for Pagets disease of bone and how is it usually found?
- pelvis, femur, skull, spine and tibia
- usually asymptomatic and found on x-ray
What are some possible complications of pagets disease of bone?
- hearing loss
- fractures
- increased bleeding risk if surgery performed on untreated pagets bone
- osteosarcoma
What are the 2 main categories of medications used to treat Pagets disease of bone?
- Bisphosphonates: Pamidronate (IV), Alendronate, Risedronate, and Zoledronate
- Calcitonin