Bone mineral pharm Flashcards
(37 cards)
drug list: minerals
calcium
phosphate
drug list- hormones
calcitonin
teriparatide
drug list: vitamin D, metabolites and analogs
- calcitriol
*cholecalciferol (vitamin D3) - ergocalciferol (vitamin D2)
calcipotriene
doxercalciferol
paricalcitol
drug list- selective estrogen receptor modulators (SERMs)
raloxifene
drug list- bisphosphonates
* alendronate etidronate ibandronate pamidronate risedronate tiludronate zoledronic acid
drug list- calcium receptor agonists
cinacalcet
other drugs
- Denosumab
estrogens
glucocorticoids
Bone Remodeling
Osteoblast-derived cytokines
RANKL binds RANK, induces osteoclast formation
Osteoprotegerin acts as decoy ligand for RANKL
Completion of resorption followed by preosteoblast invasion
Remodeling cycle ~ 6 months
Calcium and Phosphate
Calcium (Ca2+) and Phosphate (PO43-), major mineral constituents of bone
Human Adult: 1-2 kg Ca2+ and 1 kg PO43-
- 95% of Ca2+ stored in bone
- 85% of PO43- stored in bone
Absorption:
- 600-1000 mg/day of Ca2+ with 100-250 mg absorbed (net)
- Similar amount of PO43- but absorbed more efficiently
Kidney Reabsorption:
- 98% of filtered Ca2+
- 85% of filtered PO43-
Extracellular Concentrations:
- Ca2+ 8.5-10.4 mg/dL
- PO43- 2.5-4.5 mg/dL
Parathyroid Hormone (PTH)
Polypeptide hormone produced in parathyroid gland
- Activity Results:
- Increased serum calcium
- Decreased serum phosphate
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
Biotransformation of Vitamin D
Ultraviolet light
Hydroxylation in liver
Hydroxylation in kidney
consider impact of liver/ renal failure on Vitamin D
PTH effects on Intestine, kidney, bone
Intestine- inceased calcium and phosphate absorption (by increased 1,25 OH2D production)
Kidney: decreased calcium excretion, increased phosphate excretion
bone: calcium and phosphate resoprtion increased by high doeses; low doses may increase bone formation
Net effect: serum calicum increased, serum phosphate decreased
Vitamin D effects on intestine, kidney, and bone
intestine: increased calcium and phosphate absorption by 1,25(OH)2D
kidney: calcium and phosphate excretion may be decreased by 25(OH)D and 1,25(OH)2D
Bone: increased calcium and phosphate resorption by 1,25(OH)2D; bone formation may be increased by 1,25(OH)2D
Net effect: serum calcium phosphate both increased
FGF23 effects on intestine, kidney, bone
intestine: decreased calcium and phosphate absorption by decreased 1,25(OH)2D
kidney: increased phosphate excretion
bone: decreased mineralization due to hypophosphatemia
net effect: decreased serum phosphate
Teriparatide
Synthetic, recombinant PTH
Increases BMD and reduces risk or vertebral and non-vertebral fractures
MOA: intermittent PTH promotes bone growth
Therapeutic Use:
- Women – with history of osteoporotic fracture, multiple risk factors for fracture, or those intolerant or failed other drug therapy
- Men – primary or hypogonadal osteoporosis
ADRs: orthostatic hypotension, hypercalcemia, dizziness, nausea, angina
CI: those patients at increased risk of osteosarcoma
don’t give longer than 2 years
Vitamin D
MOA: increases intestinal absorption of calcium and phosphate
- Also increases bone turnover
Therapeutic Use:
- Nutritional rickets
- Metabolic rickets and osteomalacia (especially in CKD)
- Hypoparathyroidism
- Osteoporosis
Choice of Preparation:
- Otherwise healthy patients – ergocalciferol or cholecalciferol may be used
- Liver disease – 25-hydroxyvitamin D (does not require hepatic hydroxylation)
- Kidney disease +/- liver disease – calcitriol
ADRs: hypercalcemia (+/- hyperphosphatemia), nausea, vomiting, constipation
Calcitonin
Excreted by parafollicular cells of thyroid; single-chain peptide
MOA: inhibits osteoclastic bone resorption (with time also inhibits formation)
- Decreases calcium and phosphate reabsorption in kidney
Net Effects: decreased serum calcium and phosphate
PK:
- Human calcitonin t1/2 10 min; salmon calcitonin t1/2 40-50 min
Therapeutic Use:
- Disorders of increased skeletal remodeling (Paget’s disease, osteoporosis)
ADRs: nausea, hand-swelling, urticaria, intestinal cramping (rare)
Glucocorticoids
Actions Related to Bone Mineral Homeostasis:
- Antagonize vitamin D stimulated intestinal calcium transport
- Stimulate renal calcium excretion
- Block bone formation
Net Effect: decrease total body calcium stores
Therapeutic Use:
- Hypercalcemia (associated with lymphomas and granulomatous diseases)
- Vitamin D intoxication
Estrogens
MOA: prevent maturation of osteoclast precursors to mature osteoclasts
Therapeutic Use:
- Primary hypogonadism
- Post-menopausal hormone replacement therapy
- Hirsutism and amenorrhea
- Prevention of osteoporosis
ADRs: increased risk of heart disease and breast cancer, uterine bleeding, cancer (breast, endometrial), nausea, breast tenderness, hyperpigmentation, migraines, cholestasis, gallbladder disease, hypertension
CIs:
- Estrogen-dependent neoplasms
- Undiagnosed genital bleeding
- Liver disease
- History of thromboembolism
- Heavy smokers
Raloxifene
Selective Estrogen Receptor Modulator (SERM)
MOA: partial agonist in bone but does not stimulate endometrial proliferation
Therapeutic Use:
- Treatment and prevention of post-menopausal osteoporosis
ADRs: hot flashes, leg cramps, thromboembolism
CIs:
- Active or past history of thromboembolism
- Coronary heart disease or risk factors for major coronary event
Bisphosphonates: agents, MOA and PKs
Agents: alendronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, zoledronate
MOA: analogs of pyrophosphate
- P-O-P bond replaced with non-hydrolyzable P-C-P
- Concentrate at sites of active remodeling
- Decreases formation and dissolution of hydroxyapatite
- Directly inhibits osteoclasts
PK:
Food decreases absorption –> take on an empty stomach
under 10% of dose absorbed; nearly half of absorbed accumulates in bone
Bisphosphonates: therapeutic use and ADRs
Therapeutic Use:
- Osteoporosis
- Hypercalcemia associated with malignancy
- Paget’s disease
ADRs:
- Esophageal and gastric irritation (oral formulations)
- Hypocalcemia and musculoskeletal pain
- Osteonecrosis of the jaw (dentists won’t want to treat these patients)
- Subtrochanteric fractures
“Drug Holidays”
Denosumab
Fully human monoclonal antibody
MOA: binds and prevents action of RANKL. Mimics effects of osteoprotegerin.
Blocks osteoclast formation and activation
PK:
- Administered subcutaneously every 6 months
Therapeutic Use:
- Post-menopausal osteoporosis
- Cancer (prostate and breast)
ADRs: concern for immune suppression, osteonecrosis and fractures, hypocalcemia
