Drugs- Agents that affect bone mineral homeostasis (Kinder) Flashcards
raloxifene
aka Evista
Selective estrogen receptor modulators
alendronate
bisphosphonate
what regulates osteoclast production
osteoblast derived cytokines
what is the receptor for activating NF-KB (RANK)
an osteoclast protein whose expression is required for osteoclastic bone resorption
what is OPG
osteoprotegerin
produced by osteoblasts
acts as a decoy ligand for RANKL.
(1) Under conditions associated with increased bone resorption (estrogen deprivation) OPG is suppressed.
how long does the remodeling of bone cycle take
6 months
how does age related bone loss occur
vii) If replacement of resorbed bone precisely matched bone removed, remodeling would not change bone mass. However, small bone deficits persist after each cycle and life-long accumulation of these deficits leads to age-related bone loss.
how much Ca is in the diet about and how much is absorbed
600-1000 mg/day
100-250 mg absorbed in duodenum and jejunum , excreted in ileum
what percentage of filtered calcium is reabsorbed by the kidney
98%
what is the normal extracellular ca
8.5 - 10.4 mg/dL
normal extracellular phosphage levels
2.5 - 4.5 mg/dL
PTH effects on Ca and PO4
increases ca , decreased serum PO4
how does PTH affect bone
(1) PTH acts on osteoblasts to induce membrane bound and secreted soluble protein RANKL.
(2) RANKL acts on osteoclasts and osteoclast precursors to increase numbers and activity.
(3) These actions increase bone remodeling.
net effect is increased bone resorption
PTH affects on sclerostin
ii) PTH also inhibits production and secretion of sclerostin from osteocytes.
(1) Sclerostin blocks osteoblast proliferation.
(2) Thus, PTH directly increases proliferation of osteoblasts through sclerostin inhibition
PTH effects on kidney
iv) In kidney, PTH increases tubular reabsorption of Ca2+ and inhibits reabsorption of PO43-.
PTH effects on vitamin D
(1) PTH also stimulates 1,25(OH)2D production.
PTH effects on: magnesium amino acids bicarb sodium chloride sulfate
(2) Other effects: increased reabsorption of magnesium
and increased excretion of amino acids, bicarbonate, sodium, chloride, and sulfate.
what suppresses PTH production
i) Calcium-sensing receptor (CaSR) when stimulated by Ca2+ decreases PTH production.
ii) Vitamin D (1,25(OH)2D) also suppresses PTH production.
what is teriparatide
i) Synthetic, recombinant human parathyroid hormone (1-34)
ii) MOA: continuous administration of PTH causes bone demineralization and osteopenia; however, intermittent*** PTH (once daily subcutaneous injection) promotes bone growth.
what is the therapeutic use of teriparatide
iii) Therapeutic use: women with history of osteoporotic fracture, who have multiple risk factors for fracture, or who have failed (or are intolerant to) other drug therapy. Men with primary or hypogonadal osteoporosis.
(1) Has not been studied beyond two years of use – limit duration of therapy to two years.
what are the ADR’s of teriparatide
orthostatic hypotension, hypercalcemia, dizziness, nausea, hyperuricemia, and angina
what are the contraindications for teriparatide
CI: Teriparatide therapy is not advised in patients who are at an increased risk of osteosarcoma, such as those with Paget disease of the bone, unexplained elevations of alkaline phosphatase, open epiphyses, or prior radiation therapy involving the skeleton.
what does calcitriol (Vitamin D) do
augments intestinal absorption and retention of Ca2+ and PO43-.
increases bone turnover by:
i) Promoting the recruitment of osteoclast precursor cells to resorption sites.
ii) Promoting the development of differentiated functions that characterize mature osteoclasts.
iii) Inducing the synthesis of several proteins that regulate the bone mineralization process, such as RANK ligand and osteocalcin.
MOA of vitamin D analogs
i) MOA: increases intestinal absorption of Ca2+ and PO43- as well as bone turnover.
what are the therapeutic uses for vitamin D analogs
Prophylaxis and cure of nutritional rickets
Treatment of metabolic rickets and osteomalacia (particularly in the setting of chronic renal failure)
Treatment of hypoparathyroidism
prevention and treatment of osteoporosis
For pt’s who are otherwise healthy and have metabolic rickets OR osteomalacia, what vitamin D analogs should be used
(b) For patients who are otherwise healthy, ergocalciferol or cholecalciferol may be used.
For patients with liver disease, that are getting vitamin D analogs for metabolic rickets or osteomalacia, what vitamin D analogs are used?
25-hydroxyvitamin D should be used because it does not require hepatic 25-hydroxylation.
for pt’s with kidney disease who are getting treatment for metabolic rickets and osteomalacia , what vitamin D analogs are used?
calcitriol - most rapid onset of action, but associated with high incidence of hypercalcemia so follow carefully
what vitamin D analogs do you use for prophylaxis and cure of nutritional rickets
(a) The most widely used treatment for vitamin D deficiency consists of vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol), which require metabolic conversion in the liver and kidney to the most active form of vitamin D (calcitriol).
what are the ADR’s of vitamin D analogs
hypercalcemia with or without hyperphosphatemia
nausea, vomting
constipation
serious side effects:
- arryhthmias
- pancreatitis
Fibroblast growth factor 23
effects on intestine, kidney and bone? net effect?
a) Single-chain protein. Inhibits 1,25(OH)2D production and phosphate reabsorption in kidney and can lead to both hypophosphatemia and inappropriately low levels of circulating 1,25(OH)2D
a) Osteocytes and osteoblasts in bone appear to be primary site of production.
Intestine–> Decreased calcium and phosphate absorption by decreased 1,25(OH)2D production
Kidney–> Increased phosphate excretion
bone–> Decreased mineralization due to hypophosphatemia
net effect on serum levels–> Decreased serum phosphate
where does calcitonin come from
a) Excreted by parafollicular cells of thyroid; single-chain peptide.
what are the principle effects of calcitonin and what organ systems does it act on?
decrease serum calcium and phosphate by actions on bone and kidney.
i) In the bone, inhibits osteoclastic bone resorption. Although bone formation is not impaired initially after calcitonin administration, with time both formation and resorption are reduced.
ii) In the kidney, calcitonin decreases both Ca2+ and PO43- reabsorption as well as reabsorption of other ions including sodium, potassium, and magnesium.
what is the therpeutic use of calcitonin?
d) Therapeutic use: disorders of increased skeletal remodeling (Paget’s disease, osteoporosis)
what are the ADR’s of calcitonin?
e) ADRs: nausea, hand swelling, urticaria, and intestinal cramping (rare).
what are the effects of glucocorticoids on calcium
a) Antagonize vitamin D stimulated intestinal calcium transport, stimulate renal calcium excretion, and block bone formation. The ultimate effect: decrease in total body calcium stores.
what is the therapeutic use of glucocorticoids in terms of calcium control
b) Therapeutic use: reversing hypercalcemia associated with lymphomas and granulomatous disease like sarcoidosis (in which unregulated ectopic production of 1,25(OH)2D occurs), or in vitamin D intoxication.
what happens with prolonged use of glucocorticoids in adults and children
c) Prolonged administration is a common cause of osteoporosis in adults and can cause stunted skeletal muscle development in children.
what are the effects of estrogens on bone/calcium
a) Prevent accelerated bone loss during the immediate post-menopausal period. At least transiently increase bone in post-menopausal women.
estrogens reduce bone-resorbing action of PTH.
what is SERM (Selective estrogen receptor modulator)
(selective estrogen receptor modulatory)
serves as a partial agonist in bone but does not stimulate endometrial proliferation in post-menopausal women.
i) Raloxifene retains the beneficial effects on bone while minimizing the deleterious effects on breast, uterus, and cardiovascular system.
what is the therapeutic use of raloxifene (evista)
ii) Therapeutic use: treatment and prevention of post-menopausal osteoporosis.
what are the ADR’s of raloxifene
hot flashes, leg cramps, and thromboembolism
(3x risk of deep vein thrombosis and pulmonary embolism).
what are the contraindications for use of raloxifene
iv) CI: in women with active or past history of venous thromboembolism and women with coronary heart disease or risk factors for major coronary events, including stroke.
what are the three secondary hormone regulators
Calcitonin
Glucocorticoids
Estrogens
alendronate
“dronates”
bisphosphonates
MOA of bisphosphonates
analogs of pyrophosphate in which P-O-P bond replaced with non-hydrolyzable P-C-P bond
i) Their structure responsible for chelating Ca2+, which gives these agents a strong affinity for bone.
ii) Concentrate at sites of active bone remodeling; incorporated into bone until the bone is remodeled and the bisphosphonate is released back into the acid medium.
iii) Decreases the formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. Also, directly inhibits osteoclasts.
iv) Some of the newer agents appear to increase bone mineral density. May be a result of other cellular effects including inhibition of 1,25(OH)2D production and intestinal calcium transport.
how should a pt take bisphosphonates
on an empty stomach
administer with a full glass of water at least 30 minutes prior to the first meal.
what are the adverse effects of Bisphosphonates
esophageal and gastric irritation - minimize by taking full glass of water and remaining upright for 30 min
osteonecrosis of jaw (rare, more frequent with high IV doses used in bone mets and cancer induced hypercalcemia)
subtrochanteric femur fractures due to over-suppression of bone turnover
iii) Complications are rare but have led some authorities to recommend a “drug holiday” after 5 years of treatment if clinical condition warrants it (i.e. if fracture risk of discontinuing bisphosphonate is not deemed high).
what is Denosumab and what is its MOA
fully human monoclonal antibody
MOA:
binds and prevents action of RANKL
i) Mimics the effects of osteoprotegerin, reducing binding of RANKL to RANK and blocking osteoclast formation and activation (osteoclastogenesis).
what is the therapeutic use of Denosumab and how do you adminster it?
b) Therapeutic use: post-menopausal osteoporosis and some cancers (prostate and breast).
c) PK: administered subcutaneously every 6 months
what are the three main ADR’s of Denosumab?
i) A number of cells in the immune system also express RANKL suggesting there could be an increased risk of infection associated with use.
ii) Because suppression of bone turnover is similar to potent bisphosphonates, risk of osteonecrosis of the jaw and subtrochanteric fractures may be increased (although this has not been reported in clinical trials leading up to FDA approval).
iii) Can lead to transient hypocalcemia, especially in patients with marked bone loss (and bone hunger) or compromised calcium regulatory mechanisms including chronic kidney disease and vitamin D deficiency.
what is the mechanism of action of cinacalcet (Calcimimetic)
a) MOA: activates CaSR, which is widely distributed but has greatest concentration in parathyroid gland. Activation leads to inhibition of PTH secretion.
therapeutic use of cinacalcet
treatment of secondary hyperparathyroidism in chronic kidney disease and vitamin D deficiency.
ADR of cinacalcet
hypocalcemia
(do not use if initial Ca2+ < 8.4 mg/dL).
what are the DDI’s to consider with cinacalcet
e) DDI’s: drugs which interfere with calcium homeostasis
those that inhibit cinacalcet absorption (vitamin D analogs, bisphosphonates, calcitonin, glucocorticoids),
or those that interfere with metabolism (P450 inducers and inhibitors).
what are the major causes of hypercalcemia
thiazide therapy
hyperparathyroidism
cancer
what are some less common causes of hypercalcemia
hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency and immobilization.
what are the 5 main treatment approaches to hypercalcemia
Saline diuresis +/furosemide
(1) Most patients with severe hypercalcemia have a substantial component of prerenal azotemia due to dehydration which prevents kidney from compensating for the rise in serum calcium by excreting more calcium in the urine.
Bisphosphonates
Calcitonin
Phosphate –(1) Fastest and surest way to decrease serum calcium but hazardous if not done properly
Glucocorticoids
what are the risk associated with IV phosphates
sudden hypocalcemia, ectopic calcification, acute renal failure, hypotension.
tetany, paresthesias, laryngospasm, muscle cramps, seizures.
hypocalcemia
what are the major causes of hypocalcemia
b) Major causes: hypoparthyroidism, vitamin D deficiency, chronic kidney disease, and malabsorption
what is the treatment approach to hypocalcemia
Calcium IV, IM or PO
Vitamin D, calcitriol, when rapid action required (raises serum Ca within 24-48 hrs)
what is the risk with rapid infusions of calcium for treatment of hypocalcemia
cardiac arrhythmias
what are the common causes of hyperphosphotemia
common complication of renal failure
hypoparathyroidism
vitamin D intoxication
tumoral calcinosis
how do you treat primary hyperparathryoidism
surgery
vitamin D supplementation in mild deficiency
cinacalcet for secondary hyperparathyroidism
what are the treatment options for osteoporosis
x6
i) Bisphosphonates
ii) SERMs
iii) Calcium and vitamin D supplementation
iv) Teriparatide
v) Calcitonin
vi) Denosumab
first line agents (2) for Paget’s disease
calcitonin and bisphosphonates (etidronate, alendronate, risedronate, tiludronate)
where is RANK L
on the osteoblast
where is RANK
on the osteoclast
what does OPG do
suppresses the ability of RANLK to start osteoclast maturation
completion of bone resorption is followed by what
by preosteoblast invasion
what are the biotransformation steps in vitamin D
Ultraviolet light in the skin
Hydroxylation in liver (25-hydroxylase)
Hydroxylation in kidney (alpha 1 hydroxylase)
end organ impairment in the kidney? use calcitriol b/c it doesn’t need any further processing
60 year old severe inflammatory bowel disease labs Ca 7 albumin 2.7 Cr 1.1
suspect- malnutrtion/malabsorption and would like to give an intravenous calcium bolus
what is the pt’s corrected calcium?
what is the treatment approach?
what is the dose for symptomatic hypocalcemia of elemental calcium?
4-plasma albumin * 0.8 + serum calcium
So 4 - 2.7 * 0.8 + 7 = 8.04
Treatment:
Calcium (oral) and Vitamin D
oral calcium options:
- calcium carbonate- preferred
- calcium citrate- useful if the pt is on proton pump inhibitors or H2 receptor blockers
IV calcium options:
-calcium gluconate- preferred
-calcium chloride- increased risk for tissue necrosis
3x more potent than gluconate
200-300 mg of elemental calcium used is symptomatic hypocalcemia
what oral calcium supplement is preferred in pt’s on proton pump inhibitors
calcium citrate
what is normal vitamin D amounts
30-70?
65 year old post menopausal
history of HTN
Bone mineral density T scores
- 2.4 hip
- 2.6 at spine
should this pt receive calcium and vitamin D supplementation
if so, how much?
She definitely needs this !
Amounts of Vitamin for ages:
70 800 vitamin D
Amounts of Ca for ages: 19-50 1000 mg Ca 51-70 years men 1000 mg Ca 51-70 years women 1200 mg Ca >70 1200 mg Ca
she should receive 1200 mg Ca and 600 mg of Vitamin D
supplement that can cause constipation intestinal bloating and excess gas
calcium
hypotension , hypercalcemia, dizziness ADR
teriparatide
recombinant PTH, enhances remodeling
nausea and hand swelling
calcitonin
hypercalcemia, nausea, constipation
enhances intestinal absorption of calcium and phosphate
vitamin D
what is the drug with the MOA of: Estrogen receptor agonist in bone
ADR?
Raloxifene
hot flashes, leg cramps, increased risk for thromboembolism
Inhibits osteoclasts, inhibits the dissolution of hydroxyapate
what is this drug and what are the ADR’s
Alendronate
esophageal and gastric irritation
osteonecrosis of jaws
atypical femur fractures
Hypocalcemia, potential increased risk of infection and osteonecrosis
MOA of this drug?
Denosumab
binds and prevents action of RANK L
