Pharm: Agents that affect bone mineral homeostasis Flashcards
calcium
- 98% of filtered Ca2+ reabsorbed by kidney
phosphate
- 85% of filtered phosphate is reabsorbed by the kidney
teriparatide
- synthetic PTH hormone
MOA: continuous administration of PTH osteopenia; but intermittent PTH promotes bone growth
Use: osteoporosis
ADR’s: orthostatic hypotension, hypercalcemia, dizziness, nausea, hyperuricemia, angina
CI: not advised for patients who have increased risk of osteosarcoma! (Paget’s disease, high alk phos levels)
calcitonin
- hormone excreted by parafollicular cells of thyroid
MOA:
- decreases serum calcium and phosphate actions
- Bone: inhibits osteoclast bone resorption and formation over time
- Renal: decreases calcium and phosphate reabsorption and other ions like sodium, potassium, Mg+ in the kidney
Use:
- disorders of increased skeletal remodeling (Paget’s disease, osteoporosis)
ADR’s: nausea, hand swelling, urticaria, intestinal cramping
cholecalciferol
- vitamin D3 (natural)
MOA:
- increases intestinal absorption of Ca2+ and PO- as well as bone turnover
Use:
- cure of nutritional rickets
- tx for metabolic rickets/osteomalcia (no liver failure or kidney disease)
- tx of hypoparathyroidism
- prevention/tx of osteoporosis
ADR’s:
- hypercalcemia, nausea, vomiting, constipation
- ** arrhythmias and pancreatitis ***
Ergocalciferol
- vitamin D2 (plant-based)
MOA:
- increases intestinal absorption of Ca2+ and PO- as well as bone turnover
Use:
- cure of nutritional rickets
- tx for metabolic rickets/osteomalcia (no liver failure or kidney disease)
- tx of hypoparathyroidism
- prevention/tx of osteoporosis
ADR’s:
- hypercalcemia, nausea, vomiting, constipation
- ** arrhythmias and pancreatitis ***
calcitriol
- the potent vitamin D metabolite (1,25 dihydroxyvitamin D)
MOA:
- increases intestinal absorption of Ca2+ and PO- as well as bone turnover
Use: *** used for RENAL and LIVER failure **
- cure of nutritional rickets
- tx for metabolic rickets/osteomalcia
- tx of hypoparathyroidism
- prevention/tx of osteoporosis
ADR’s:
- hypercalcemia, nausea, vomiting, constipation
- ** arrhythmias and pancreatitis ***
raloxifene
- selective serotonin (estrogen) receptor modulator: SERM
MOA: serves as an agonist in bone of estrogen, but doesn’t stimulate the endometrium, cause problems in breasts or CV system
USE: tx and prevention of post-menopausal osteoporosis
ADR’s: hot flashes, leg cramps, thromboembolism ** (3x risk of DVT and PE!!!)
CI: hx of DVT or coronary heart disease, or risk factors of stroke
alendronate
- biphosphonate
MOA: analog of pyrophosphate in which P-O-P is replaced by P-C-P bond (incorporates itself into the bone and inhibits osteoclasts)
- Ca2+ chelation in sites of active bone remodeling
- inhibits osteoclasts
- increased bone mineral density
USE:
- osteoporosis
- hypercalcemia assoc. w/ malignancy
- Paget’s disease
ADR’s:
- esophageal/gastric irritation in oral formations
- osteonecrosis of jaw
- subtrochanteric femur fractures (d/t oversupression of bone formation)
denosumab
MOA: monoclonal antibody that binds and prevents action of RANKL
- mimics osteoprotegerin by reducing binding of RANKL to RANK and blocking osteoclast formation and activation (prevents osteoclastogenesis)
USE: post-menopausal osteoporosis
- some breast/prostate cancers
PK: subcutaneous every 6 mos
ADR’s: well tolerated but…
- can increase risk of infection d/t interference w/ immune system RANKL expression
- risk of osteonecrosis of jaw/subtrochanter
- can lead to transient hypocalcemia
normal extracellular calcium levels?
8.5-10.4 mg/dL
normal extracellular phosphate levels?
2.5-4.5 mg/dL
glucocorticoids?
- antagonize vit D stimulated intestinal Ca2+ transport
- stimulate renal calcium excretion
- block bone formation
= decreased total body calcium stores
USE: reversing hypercalcemia assoc. w/ lymphomas/granulomatous sarcoidosis or Vit D intoxication
estrogens?
prevent accelerated bone loss by reducing action of PTH
MOA: prevent maturation of osteoclast precursors to mature osteoclasts
Use:
- primary hypogonadism
- post-menopausal hormone replacement
- hirsutism and amenorrhea
ADR’s: increased risk of cardiovascular risks and breast cancer (only used in pts. that are postemenopausal w/ significant hotflashes, and already have osteoporosis)
CI:
- liver disease, undiagnosed genital bleeding, hx of thromboembolizm, heavy smokers
fibrobastic growth factor 23?
- single chain protein that inhibits 1,25 (OH)2 D production and inhibits phosphate reabsorption in kidney
- intestine: decreases calcium and phosphate absorption by inhibiting production of Vit D
- kidney:: increased phosphate excretion
- bone: decreased mineralization due to hypophosphatemia
can cause hypophosphatemia and inappropriate low levels of Vit D
effects of hypercalcemia?
CNS depression, coma, potentially lethal
causes of hyperCa?
thiazide therapy, hyperparathyroidism, cancer, hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency
- calcium level up to 12 is considered mild
- calcium 12-14 = moderate level
- calcium >14 = severe:
tx of hyperCa?
this is treatment of severe calcium
- saline diuresis +/- furosemide
- bisphosphonates - seen effects in several days
- calcitonin - effects seen in 4-6 hours
- phosphate: fastest and surest way to decrease calcium - but has risks of servere hypocalcemia, ARF, hypotension
- glucocorticoids
effects of hypocalcemia?
neuromuscular tetany, paresthesias, laryngospasm, mm. cramps, seizures
causes of hypoCa?
hypoparathyroidism, Vit D deficiency, CKD, malabsorption
tx of hypoCa?
- Calcium IV along w/ Vit D calcitrol
hyperphosphatemia?
- common complication of renal failure
- tx: dietary phosphate restriction, phosphate binding gels, calcium supplements
tx of hypoparathyroidism?
calcium and vit D supplementation
osteoporosis
- abnormal loss of bone predisposing pts. to bone fractures
- most common in post-menopausal women
- may be d/t prolonged glucocorticoid use, endocrine disease, malabosprtion syndrome, alcohol or cigarette smoking
tx options:
- bisphosphonates (alendronate), SERM’s (raloxifene), Ca2+ and Vit D supplements, teriparatide, calcitonin, denosumab
Paget’s disease tx?
calcitonin and bisphosphates (should not exceed 6 mos, but can be repeated after 6 mos) are first line tx
basic bone phys?
PTH and 1,25 (OH)2 D – stimulate osteoblast and osteoclast formation
- osteoblasts stimulate osteoclast formation through RANKL and MCSF
- (Osteoprotegerin) OPG inhibits osteoclast formation by acting as decoy ligand for RANKL
- estrogen, bisphosphonates and calcitonin inhibit osteoclast breaking down calcified bones
PTH
- increased serum calcium
- decreased serum phsophate
Actions on bone:
- Indirectly increases activity and number of osteoclasts
- Acts on osteoblasts –> induces RANKL
- RANKL increases osteoclast activity and number
- Increases bone remodeling
- Net effect = bone resorption (but low, intermittent doses increase bone formation)
Actions in kidney:
- Increases reabsorption of calcium; inhibits reabsorption of phosphate
- Stimulates 1,25(OH)2D (calcitriol) production
Vitamin D
- Applied to natural cholecalciferol (vitamin D3) and plant-derived ergocalciferol (vitamin D2)
- Activity results:
- Increased calcium and phosphate
- Increased bone turnover
Actions in intestine:
- Augmented absorption of calcium and phosphate
Actions on bone:
- Promotes recruitment of osteoclast precursors
- Induces RANKL
Requires three steps of biotransformation:
- UV light
- livery hydroxylation
- kidney hydroxylation
case 1: 60 y/o male w/ severe IBD. lab values: Ca2+ is 7, physician suspects malnutrition/malabsorption. they have albumin of 2.7 and Scr of 1.1
corrected calcium: (4-albumin)*.8 + serum calcium = 8 mg/dL
For calcium deficiency:
- initiate oral calcium carbonate first (preffered)
- or initiate calcium gluconate IV
65 y/o female w/ hx of HTN, BMD T-score is -2.4 at hip and -2.6 at spine. should patient receive calcium and vit D supplementation?
yes she should if she is depleted
- recommend weight bearing exercise
- mm. strengthening
- avoid smoking and consume only moderate amounts of alcohol
When is drug therapy indicated?
- if pt. has hip/spine fracture
- if patient has -2.5 T score
- if patient has T score greater than -1 and have increased risk of osteoporosis fracture
T score rating
+1 to -1 = normal
T-score between −1 and −2.5 indicates that you have low bone mass, although not low enough to be diagnosed with osteoporosis.
T-score of −2.5 or lower indicates that you have osteoporosis.
AE of constipation, intestinal bloating excess gas
Calcium
AE of hypotension, hypercalcemia and dizziness
synthetic PTH - teriparatide
AE of nausea and hand swelling
calcitonin - inhibits osteoclastic bone resoprtion
AE of hot flash, leg cramps, thromboembolism
raloxifene = estrogen receptor agonist in bone
AE of esophageal and gastric irritation
alendronate: inhibits osteoclasts and inhibits dissoolution of hydroxyapatite
AE hypocalcemia, potential increased risk of infection and osteonecrosis
Denosumab - binds and prevents action of Rank L
