Drugs that affect bone mineral homeostasis Flashcards
Calcium and Phosphorus
The major elements of bone.; mechanical strength of skeleton and normal function of other cells.
Primary Regulators
Parathyroid hormone (PTH)
Vitamin D
Fibroblast Growth factor 23 (FGF23)
Secondary Regulators
Calcitonin
Glucocorticoids
Estrogen
Parathyroid Hormone
- An 84-amino-acid peptide.
- Acts on membrane G protein-coupled receptors to increase cyclic adenosine monophosphate (cAMP) in bone and renal tubular cells.
PTH in kidney
- Inhibits calcium excretion.
- Promotes phosphate excretion.
- Stimulates the production of active vitamin D metabolites.
PTH in bone
- Promotes bone turnover by increasing the activity of both osteoblasts and osteoclasts.
- Osteoclast activation is not a direct effect and instead results from PTH stimulation of osteoblast formation of RANK ligand.
RANKL- A member of TNF cytokine family that stimulates the activity of mature osteoclasts and the differentiation of osteoclast precursors.
Hyperparathyroidism.
- Net effects of elevated PTH is incfeased bone resorption, hypercalcemia and hyperphosphatemia.
- However low intermittent doses of PTH produce a net increase in bone formation; this is the absis of use of Teriparatide.
- Teriparatide is a recombinant truncated form of PTH, for paranteral treatment of osteoporosis.
The synthesis and secretion of PTH is primarily regulated by?
- Serum concentration of free ionized calcium.
- A drop in free ionized calcium stimulates PTH release.
- Active metabolites of Vitamin D play a secondary role in regulating PTH secretion by inhibiting PTH synthesis.
Vitaimin D
- A fat soluble vitamin
- Can be synthesized in the skin from 7-dehydrocholestrol under the influence of UV.
- Can be absorbed in diet in the natural form Cholecalciferol or the plant form Ergocalciferol.
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What active metabolites are formed in the liver and kidney respectively?
Liver: 25-hydroxyvitamin D or calcifediol.
Kidney: 1, 25-dihydroxyvitamin D or calcitriol.
Renal synthesis of active vitamin D metabolites is stimulated by?
PTH
Synthesis of 1,25-dihydroxyvitamin D2 is inhibited by?
Phosphate, FGF23 and Vitamin D metabolites.
Use of topical formulations of Vitamin D
Used in psoriasis; a hyperproliferative skin disorder.
1a-Hydroxyvitamin D2 (Doxercalciferol)
A prodrug that is converted in the liver to 1,25-dihydroxyvitamin D.
19-nor-1,25-dihydroxyvitamin D2 (paracalcitolol) and calcipotriene (calcipotriol) are?
Analogs of calcitriol
Uses of calcitriol analogs.
- Doxercalciferol, paricalcitolol and calcipotriene; all cause less hypercalcemia and in patients with normal enal function, less hypercalcuria than calcitriol.
- Oral and parenteral deoxycalciferal and oral paricalcitol are approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease.
- Calcipotriene (calcipotriol) is approved for topical treatment of psoriasis.
- These and other analogs are being investigated for use in various malignancies and inflammatory disorders.
Fibroblast Growth factor 23 (FGF 23)
- Secreted by osteocytes in bone.
- Inhibits 1,25(OH)2D production and phosphate reabsortion in kidney.
- Not used as a drug.
Calcitonin
- A peptide hormone secreted by the thyroid gland.
- Decreases serum calcium and phosphate by inhibiting bone resorption and inhibiting renal excretion of these minerals. Bone formation is not impaired initially, but ultimately both formation and resorption are reduced.
- The hormone has been used in conditions in which an acute reduction of serum calcium is needed (eg, Paget’s disease and hypercalcemia).
- Calcitonin is administerd by injection or as a nasal spray.
- Calcitonin is approved for treatment of osteoporosis and has been shown to increase bone mass and to reduce spine fractures.
- However, it is not as effective as teriparatide or bisphosphonates.
Why is salmon calcitonin preferred?
Although human calcitonin is available, salmon calcitonin is most often selected for clinical use because of its longer half-life and greater potency.
Glucorticoids
The glucocorticoids inhibit bone mineral maintenance. As a result, chronic systemic use of these drugs is a common cause of osteoporosis in adults.
However, these hormones are useful in the intermediate-term treatment of hypercalcemia.
Estrogens
Estrogens and selective estrogen receptor modulators (SERMs; eg, raloxifene) can prevent or delay bone loss in postmenopausal women.
Their action involves the inhibition of PTH-stimulated bone resorption.
Nonhormonal Agents
- Biphosphates
- Fluoride
- Calcimetics
Biphosphonates
> alendronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronic acid
Are short-chain organic polyphosphate compounds that reduce both the resorption and the formation of bone by an action on the basic hydroxyapatite crystal structure.
Comlex cellular effects of biphosphonates.
- Effects on vitamin D production.
- Calcium absorption from the GI tract.
- Direct effects on osteoclasts, including inhibition of farnesyl pyrophosphate synthase, an enzyme that appears to play a critical role in osteoclast survival.
- Used to manage the hypercalcemia associated with some malignancies and to treat Paget’s disease.
- Chronic bisphosphonate therapy is used commonly to prevent and treat all forms of osteoporosis. It has been shown to increase bone density and reduce fractures
Biphosphonates; Oral medication.
- Etidronate and the other bisphosphonates listed above are available as oral medications.
- Oral bioavailability of bisphosphonates is low (<10%), and food impairs their absorption.
- Bisphosphonate treatment of osteoporosis is accomplished with:
- Daily oral dosing (alendronate, risedronate, ibandronate).
- Weekly oral dosing (alendronate, risedronate).
- Monthly oral dosing (ibandronate).
- Quarterly injection dosing (ibandronate).
- Annual infusions (zoledronate).
Primary toxicity of low oral biphosphonate doses used for osteoporosis.
- Gastric and esophageal irritation.
- The higher doses of bisphosphonates used to treat hypercalcemia have been associated with renal impairment and osteonecrosis of the jaw.
Rank Ligand (RANKL) inhibitor
- Denosumab is a human monoclonal antibody that binds to and prevents the action of RANKL; Denosumab inhibits osteclast formation and activity.
- As effective as bisphosphonates.
- Used for treatment of postmenopausal osteoporosis.
- Denosumab is administered subcutaneously every 6 mo, which avoids gastrointestinal side effects.
- The drug appears to be well tolerated, but there could be an increased risk of infection due to RANKL’s role in the immune response.
Calcimimetics
- Cinacalcet lowers PTH by activating calcium-sensing receptor in the parathyroid gland.
- It is used for oral treatment of secondary hyperparathyroidism in chronic kidney disease and for the treatment of hypercalcemia in patients with parathyroid carcinoma.
- Its toxicities include hypocalcemia and adynamic bone disease, a condition of profoundly decreased bone cell activity.
Fluoride
- Appropriate concentrations of fluoride ion in drinking water or as an additive in toothpaste have a well-documented ability to reduce dental caries.
- Chronic exposure to the ion, especially in high concentrations, may increase new bone synthesis. It is not clear, however, whether this new bone is normal in strength.
- Clinical trials of fluoride in patients with osteoporosis have not demonstrated a reduction in fractures.
- Acute toxicity of fluoride (usually caused by ingestion of rat poison) is manifested by gastrointestinal and neurologic symptoms.
Strontium Ranelate
Strontium ranelate, an organic ion bound to 2 atoms of strontium, promotes osteoclast apoptosis and increases concentrations of bone formation markers; it is used in Europe for treatment of osteoporosis.
Gallium Nitrate
Gallium nitrate is effective in managing the hypercalcemia associated with some malignancies and possibly Paget’s disease. I
t acts by inhibiting bone resorption.
To prevent nephrotoxicity, patients need to be well hydrated and to have good renal output.
Plicamycin (mithramycin)
The antibiotic plicamycin (mithramycin) has been used to reduce serum calcium and bone resorption in Paget’s disease and hypercalcemia.
Because of the risk of serious toxicity (eg, thrombocytopenia, hemorrhage, hepatic and renal damage), plicamycin is mainly restricted to short-term treatment of serious hypercalcemia.
Diuretics
Several diuretics, most notably thiazide diuretics and furosemide, can affect serum and urinary calcium levels.
Sevelamer
The phosphate-binding gel sevelamer is used in combination with calcium supplements and dietary phosphate restriction to treat hyperphosphatemia, a common complication of renal failure, hypoparathyroidism, and vitamin D intoxication.
