SM160 Calcium/PTH/Bone Pharm Flashcards
Normal serum calcium
8.5-10.5 mg/dL
Calcium forms in blood
50% ionized (active), 10% bound to anions, 40% protein bound
Active form of vit. D? Storage form?
Active: calcitriol - 1,25(OH)2D3
Storage: cholecalciferol/calcidiol - 25(OH)D3
Where is calcium absorption vit. D dependent?
Proximal duodenum
What type of diuretic gives you hypocalcemia and what type gives you hypercalcemia?
Loops cause hypocalcemia, thiazides cause hypercalcemia
PTH actions on kidney
Increased calcium absorption, potassium loss, stimulates 1alpha-hydroxylase
Calcium form in bone
Hydroxyapatite: Ca10[PO4]6[OH]2
Cell lineage of osteoclasts
Monocyte (related to macrophages)
Osteoclast differentiation
Osteoblasts express RANK-L, which stimulates osteoclasts and osteoclast precursors via the RANK receptor
Osteoprotegerin
RANK-L antagonist produced by osteoblasts, ratio of RANK-L to osteoprotegerin is important
Osteoclast action
Resorb collagenous bone matrix by secreting acid and proteases
Osteoblast action
Produces alkaline phosphatase (elevation indicates active osteoblasts), collagen (combines with hydroxyapatite to form bone), osteocalcin
Also promotes osteoclast differentiation, survival, and activity via RANK-L
Osteoblast stimulants
IGF-1, bone morphogenetic proteins, wnt signaling pathway
Osteocyte actions, effect on osteoblasts
Sense mechanical load
Produce sclerostin to inhibit wnt signaling and osteoblast differentiation (if you could block this you could stimulate bone formation)
Osteoporosis
Systemic condition in which osteoblastic activity can’t keep pace with osteoclastic activity
Results in loss of mineral and matrix, susceptibility to fracture
Paget’s disease of bone
Locally increased osteoclast activity is followed by increased osteoblast activity
Results in abnormal bone formations
Vit. D synthesis
Starts with cholesterol, turned into Vit. D3 in skin (cholecalciferol - UVB light required), D3 is converted into 25(OH)D (calcidiol) in the liver and then into 1,25(OH)2D3 (calcitriol) in the kidney by 1a-hydroxylase
Vit. D/calcitriol actions
Stimulates intestinal Ca++ and phosphate absorption in the proximal duodenum, blocks PTH
Disease of deficient vit. D? Excess vit. D?
Deficiency: rickets and osteomalacia
Excess: hypercalcemia, osteoclastogenesis
Indications for calcitriol and different forms available
Alphacalcidol: secondary hyperparathyroidism resulting from renal disease and impaired renal 1-hydroxylation (doesn’t require hydroxylation)
Calcipotriol (topical): proriasis
(Last 3 are in learning guide, not in slides)
Ergocalciferol: hypocalcemia, rickets, osteomalacia, hypoparathyroidism
Doxercalciferol: secondary hyperparathyroidism
Paracalcitol and 22-oxocalcitriol: suppress PTH with minimal effects on Ca and P, used for secondary hyperparathyroidism
Vit. D/calcitriol pharmacokinetics
Oral, bound to alpha-globulin, inactivated by kidney, hepatic elimination
Vit. D/calcitriol major side effect
Hypercalcemia
Treatment: stop drug, low calcium diet, glucocorticoids, fluids
PTH generic drug name
Teriparatide
What can suppress PTH?
Calcium (+ calcimimetics) via CaSR and vit. D (calcitriol)
Cinacalcet: drug type, mechanism, indication, side effects
Calcimimetic
Activates CaSR to suppress PTH secretion
Hyperparathyroidism
Hypocalcemia, adynamic bone disease
PTH actions on bone: continuous exposure vs. intermittent exposure
Continuous exposure: bone loss due to increased RANK-L expression
Intermittent exposure: bone formation from decreased osteoblast apoptosis, increased osteoblast differentiation, and sclerostin suppression
Teriparatide: use, limitations
Osteoporosis
Hypercalcemia and osteosarcoma risk (though not yet seen in humans)
PTHrP
Associated with hypercalcemia seen in malignancy
Calcitonin: mechanism, use, limitations
Acts on mature osteoclasts via GPCR to inhibit bone resorption
Paget’s disease, hypercalcemia, and a minor role for osteoporosis
Low efficacy, can’t give orally, resistance develops
Calcitonin-gene related peptide (CGRP): action, use
Potent vasodilator
Migraines
Estrogen actions on bone
Inhibits bone resorption: less IL-6, more osteoprotegerin (RANK-L antagonist), more apoptosis of osteoclasts
Glucocorticoids influence on calcium
Blocks absorption in the gut, block reabsorption in the kidney. Long-term can cause osteoporosis.
FGF-23: what secretes it, action
Secreted by osteoblasts and osteoclasts in response to elevated calcitriol
Increases phosphate excretion in the kidney
Estrogen use, role of progestin?
Prevention of postmenopausal bone loss
Progestin helps to prevent uterine hyperplasia and malignant changes
Role of androgens in bone health
Androgens are aromatized to estrogen in bone, men with aromatase deficiency can get osteoporosis
Raloxifene: drug type, mechanism, indications, side effects
SERM (selective estrogen response modulator)
Mechanism: estrogen agonist in bone, antagonist in breast
Uses: prevent postmenopausal osteoporosis and reduce the risk of bone metastasis from breast cancer
Side effects: thromboses and hot flashes
Contraindication: women that want to get pregnant
Bisphosphonates: examples, mechanism, uses, side effects
Alenodrate (plus other -dronates), zoledronic acid
Pyrophosphate analogs, bind hydroxyapatite in bone, inhibit osteoclast activity
Paget’s, osteoporosis, hypercalcemia, bone metastases
GERD, esophageal irritation, osteonecrosis of the jaw
Denosumab: mechanism, actions, use, side effects
Monoclonal Ab against RANK-L
Inhibits osteoclast differentation, function, and survival, increasing bone mineral density
Uses: osteoporosis, bone metastases
Side effects: hypocalcemia, rash, osteonecrosis of the jaw, immunosuppression
What is the only currently used anabolic therapy for osteoporosis?
Teriparatide (PTH)
