B.20 Flashcards
gents affecting bone mineral homeostasis
- Analogs: Cholecalciferol (vitamin D analog), Teriparatide (PTH analog)
- SERM: Raloxifen
- mAb against RANK-L: Denosumab
- Bisphosphonates: Zoledronate, Alendronat
Cholecalciferol, Calcitriol
MOA: Vitamin D analog;
Kinetics: Cholecalciferol (→lipophilic, p.o adm, slow onset, accumulates in adipose tissue), Calcitriol (→hydrophilic, faster onset, quicker elimination);
IND: Cholecalciferol (→osteoporosis, vitamin D substitution), calcitriol (→renal osteodystrophy);
SEs: hypercalcemia (rare!), Hypercalciuria (common→ formation of kidney stones), nephrocalcinosis (→↓kindey function)
Teriparatide
MOA: PTH1-34 analog;
Kinetics: adm. s.c, in intermittent dosing (leads to more bone formation effect), T1/2 1h, can only be given for 2 years (b/c it can lead to osteosarcoma);
IND: Osteoporosis; SEs: GI disturbances, headache, bone pain, dizziness
Raloxifen
MOA: SERM (→acts on estrogen receptors, in some organs they act as agonists (e.g. bone) and in some as antagonists (e.g. breast/endometrium));
Kinetics: it’s efficacy on bone is equal to that of estrogen;
IND: Osteoporosis (protect against spine fractures but not hip fractures) ;
SEs: increased thromboembolic risk
Zoledronate, Alendronate
MOA: Bisphosphonates, bind bone mineral components→osteoclasts eat it→induce apoptosis in osteoclasts (nitrogen-containing bisphosphonates inhibit the activity of farnesyl pyrophosphate synthase and by this the mevalonic acid pathway);
Kinetics:
-Zoledronate (given i.v every 3/6/12 months),
-Alendronate (given p.o daily/weekly). poor BAp.o (take on empty stomach and no food/drinks for 30min), not metabolized, renal excretion, binds to bone→T1/2 10-25years (effects are still there years after therapy as stopped);
IND: osteoporosis (bisphosphonates are the most effective inhibitors of bone resorption), Bone metastasis;
SEs: Osteonecrosis (mainly in the jaw, can be triggered by dental procedues), GI mucosal irritation/GERD, Atypical bone structure (→pathological fractures)
Denosumab
MOA: mAb against RANK-L;
Kinetics: s.c adm. every 6 months (for osteoporosis) or every 4 weeks (for tumor metastasis);
Advantage: faster onset than bisphosphonates, less atypical bone structure, combination with PTH analog may have additive benefits (better than PTH analog with bisphosphonates);
Disadvantage: higher risk of hypercalcemia (in chronic kidney disease or malabsorption), effects wear off as soon as therapy stops (bisphosphonates stay for years after);
IND: osteoporosis, bone metastasis;
SEs: peripheral edemas, HSR (mainly skin related onex), GI disturbances
what should be prescribed to all osteoporosis patients?
PTH and vitamin D substitution
what stimulates bone formation and bone resorption, at the level of the bone?
PTH and vitamin D
Hormone replacement therapy in osteoporosis treatmen
- Hormone replacement therapy (HRT), increases BMD, decreases bone turnover and the number of bone fractures.
- Estrogen (combined with progestin if the uterus is intact) increases the risk of breast cancer, may enhance the risk of CV diseases (e.g. thromboembolism)
Mechanisms contributing to bone mineral homeostasis
Gut: Vitamin D (→↑Ca2+ and PO43- absorption)
Bone: Vitamin D and PTH ↑bone turnover
Kidney: Vitamin D (→↓Ca2+ and PO43- excretion) and PTH (→↓Ca2+ excretion and ↑PO43- excretion), Calcitonin (only in very very high doses!→↑Ca2+ excretion)
Osteoporosis
A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration → increase in bone fragility → FRACTURE
Parathyroid hormone (PTH)
Consists of 84 amino acids; PTH 1-34 amino acids is fully active
It’s secretion is regulated by:
1. Ca2+ level: via Ca2+ sensitive protease, Ca2+ sensing receptor → reduces PTH secretion
2. Vitamin D → suppresses PTH production
Effects: increases serum Ca2+ / decreases serum PO43-
Risk factors for osteoporosis
- Genetic factors
- Environmental factors (e.g. smoking, alcohol, physical inactivity, thin habitus, low body weight, low Ca2+ intake and little exposure to sunlight)
- Menstrual status (menopause < 45yr, previous amenorrhea)
- Drug therapy (GLUCOCORTICOIDS, antiepileptic drugs-phenytoin, excessive substitution therapy with thyroxine, hydrocortisone, anticoagulants-heparin, dicoumarine derivatives)
- Endocrine (hyperparathyroidism, thyrotoxicosis), GI (malabsorption), Rheumatologic, Hematologic diseases
Secondary hormonal regulation of bone mineral homeostasis
- Calcitonin
- Glucocorticoids
- Estrogens
- Calcitonin
- Secreted by the parafollicular cells of the thyroid gland
- Lowers serum Ca2+ and PO43-
- Inhibits osteoclastic bone resorption
- At long term inhibits both formation and resorption (not used in osteoporosis)
