Bone mineral pharm Flashcards
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
Cinacalcet
MOA: activates calcium sensing receptor (CaSR), highest concentration in parathyroid gland, which leads to inhibition of PTH secretion
PK:
- t1/2 30-40 hours; eliminated by renal excretion
- CYP3A4, CYP2D6, and CYP1A2 metabolism
Therapeutic Use:
- Secondary hyperparathyroidism in CKD
- Vitamin D deficiency
ADRs: hypocalcemia
DDIs:
- Drugs which inhibit calcium homeostasis
- Those that inhibit drug absorption
- Those that interfere with metabolism
treating hypercalcemia
isotonic saline- restores intravascular volume, increases urinary calcium excretion (hours)
calcitonin- inhibits bone resorption via intererence with osteoclast function, promotes urinary calcium excretion (4-6 hours)
bisphosphonates- inhibit bone resorption via interference with osteoclastr recruitment and function (24-72 hours)
loop diuretis- increase urinary calcium excretion via inhibition of calcium reabsorption in the loop of henle (hours)
glucocorticoids- decrease intestinal calcium absorption, decrease 1,25 dihydroxyvitamin D production by activated mononuclear cells in patients with granulomatous diseases or lymphoma (2-5 days)
Calcimimetics- calcium sensing receptor agonist, reduces PTH (parathyroid carcinoma, secondary hyperparathyroidism in CKD) (2-3 days)
dialysis- low or no calcium dalysate (hours)
equation for corrected calcium
4-plasma albumin (g/dL) * .8 + serum calcium
treating Hypocalcemia
Treatment Approach: calcium and vitamin D
Oral Calcium: Calcium carbonate (40% calcium) – preferred Calcium lactate (13% calcium) Calcium phosphate (25% calcium) Calcium citrate (21% calcium)
Intravenous Calcium:
Calcium gluconate – preferred
Calcium chloride- has to be given IV and can cause tissue necrosis
Vitamin D Deficiency
Optimal Vitamin D Level: controversial
- IOM sets lower limit at 20 ng/mL
- Endocrine society lower limit is 30 ng/mL
Causes of Deficiency:
- Decreased intake or absorption
- Reduced sun exposure
- Increased hepatic catabolism
- Decreased endogenous synthesis (↓ 25-hydroxylation in liver or ↓ 1-hydroxylation in kidney)
- End-organ resistance to vitamin D
Treatment Approach:
- Vitamin D2 or D3 in high doses for several weeks followed by maintenance dosing
- Diet should contain adequate amount of calcium
best agent for osteoporosis
teriparatide
other agents don’t do as well AND tend to plateau after a while
what supplemental MOA causes constipation, inestinal bloating, and excess gas?
calcium
what is the MOA of Teriparatide?
synthetic PTH, enhances remodelling
what is the MOA of calcitonin?
inhibits osteoclastic bone resorption
What enhances intestinal absorption of calcium and phosphate but has adverse effectsof hypercalcemia, nausea, and constipation?
Vitamin D
what are the adverse effects of raloxifene? it is an estrogen receptor agonist in bone
hot flash
leg cramps
thromboembolism
What adverse effects of alendronate? It inhibits osteoclasts, inhibits dissolution of hydroxyapatite
esophageal and gastric irritation
what is the MOA of enosumab, which has the adverse effects of hypocalcemia, potentially increasing the risk of infection and osteonecrosis?
binds and prevents action of RANKL
