Bone Mineral Homeostasis Drugs Flashcards
Physiological roles:
- Bone formation
- Neuronal excitability
- Neurotransmitter release
- Muscle contraction
- Membrane integrity
- Blood coagulation
Clinical uses:
- IV: to treat severe hypocalcemia (don’t inject into muscle)
- Oral dietary supplement: Adults (1000 mg); > 50 yo (1200 mg); Vit D is necessary for optimal absorption
Other:
- regulates PTH secretion: high serum Calcium inhibits PTH secretion
- Vit D: high serum calcium inhibits calcitriol formation in the kidneys, and stimulates production of 24,25(OH)2D inactive vitamin D
Calcium
Recombinant PTH 1-34
- Clinical use: Osteoporosis; thought to preferentially induce osteoblast activity
- Mech: release low, intermittent levels of PTH, which stimulates osteoblasts
At level of kidney (works like PTH):
- increases Calcium resabsorption in DCT
Adverse effects: increased risk of osteosarcoma
Teriparatide
- Necessary for calcium absorption
- Net effect: increase serum calcium and phosphate concentrations
- Calcitriol: 1,25-(OH)2 D3: Hormonally active form (formed in the kidneys, catalyzed by PTH), used for rapid action (24-48 hours)
- Induces osteoclast differentiation
- used in patients with renal failure
Clinical use:
- administered with Calcium to treat hypocalcemia –> increases calcium absorption from the gut
- hypoparathyroidism
Affects on Ca and phosphorus
- increases Calcium absorption from gut
- increases reabsorption of both calcium and phosphorus (contrast with PTH)
Vitamin D3 (Cholecalciferol)
Nitrogen-containing Bisphosphonate: able to inhibit cholesterol synthesis
Clinical use:
- osteoporosis
- Paget’s disease
ADME:
- absorption is poor; give on empty stomach
- esophagitis common: give sitting up
Adverse: reported incidences of severe muscle, bone or joint pain
- Long term therapy (> 4 years) not beneficial, and may increase risk of fracture
Alendronate
Nitrogen-containing Bisphosphonate: able t inhibit cholesterol synthesis
Dose: injection every 3 months
Ibandronate
Nitrogen-containing Bisphosphonate: able t inhibit cholesterol synthesis
Dose: once a month
Risedronate
Clinical use: block bone resorption
- treat hypercalcemia
- treat Paget’s disease
- osteoporosis
- secreted by parafollicular cells of thyroid at high serum calcium levels
- also found in salmon (don’t need to use human calcitonin)
Mech: decrease bone resorption of calcium
- opposes the actions of PTH
- if prolonged inhibition of bone resorption, bone formation will also be reduced
Calcitonin
Clinical use: Prevent accelerated bone loss in post-menopausal women
Mech: inhibit osteoclasts
- upregulates decoy receptor Osteoprotegerin (OPG), which binds RANKL
Risks/Adverse effects:
- coronary event
- stroke
- pulmonary emboli
- breast cancer
Estrogen
- selective estrogen receptor modulator
Benefit: reduced risk of breast or endometrial cancer
Adverse: worsening vasomotor symptoms
Raloxifine
- an antibody to RANKL
Possible use:
- Osteoporosis
- inhibit fractures
Mech:
- Mimics effects of OPG, blocking osteoclast formation and activation
- Increases BMD, decreasing bone turnover
Denosumab
- Clinical use: treatment for hypercalcemia
Mech: mimics stimulatory effect of calcium-sensing receptors (that measure serum calcium levels) to inhibit PTH secretion
- allows inhibition of PTH at lower concentrations of real calcium
Cinacalcet
- specialized fibroblasts that secrete and store the organic matrix (mostly collagen)
- activated by TGF-Beta and IGF-1 to form bone
Osteoblasts
- proteins that help osteoblast precursors differentiate into active osteoblasts
Bone Morphogenic proteins
- Produced by osteoblasts
- Upregulated by NF-kB, also known as osteoclast differentiation factor
- Upregulated by PTH, TGF-Beta or shear stress
RANKL
- carry out resorption
- formed by fusion of cells derived from hematopoetic stem cells related to phagocytes
- RANKL (ODF) + IL-1 activate osteoclast precursors
Osteoclasts
