Drugs acting on bone metabolism Flashcards
What are the main minerals in bone?
Calcium and phosphates
What are the main cells in bone homeostasis?
osteoblasts,
osteoclasts and osteocytes.
What are osteoblasts?
Osteoblasts are bone-forming
cells: they secrete important
components of the extracellular
matrix-the osteoid.
What are Osteoclasts?
Osteoclasts are multinucleated
bone-resorbing cells.
What are osteocytes?
Osteocytes are derived from the osteoblasts, which, during the formation of new bone, become embedded in the bony matrix and differentiate into osteocytes. These cells form a connected cellular network that, along with the nerve fibers in bone has a role in the response to mechanical loading.
What is osteoid?
Osteoid is the organic
matrix of bone and its
principal component is
collagen.
What is bone remodeling?
The process of remodelling involves: • Two main cell types: osteoblasts and osteoclasts • Variety of cytokines • Bone minerals-particularly calcium and phosphate • The actions of several hormones: Parathyroid hormone (PTH) Calcitonin The vitamin D family Estrogens Growth hormone Steroids
What is the action of cells and cytokines?
The osteoblast expresses a surface ligand, the RANK ligand (RANKL):
• Expression is stimulated by calcitriol, parathyroid hormone (PTH), cytokines
and glucocorticoids
RANKL interacts with a receptor on the osteoclast termed RANK (receptor activator of nuclear factor kappa B). The result is: • Differentiation and activation of the osteoclast progenitors to form mature osteoclasts; • Fusion of osteoclasts occurs to give giant multinucleated bone-resorbing cells.
The osteoblast also releases ‘decoy’ molecules of osteoprotegerin (OPG),
which can bind RANKL and prevent activation of the RANK receptor.
Bisphosphonates inhibit bone resorption
by osteoclasts.
Anti-RANKL antibodies (e.g.
denosumab) bind RANKL and prevent
the RANK-RANKL interaction.
What are the hormones involved in bone metabolism?
The actions of several hormones: Parathyroid hormone (PTH) Calcitonin The vitamin D family Estrogens Growth hormone Steroids
What is the function of Parathyroid hormone?
Mobilises Ca2+ from bone
Promotes its reabsorption by the
kidney
Stimulates the synthesis of calcitriol,
which in turn increases Ca2+
absorption from the intestine and synergises with PTH in mobilizing bone Ca2+
Promotes phosphate excretion
• Net effect – to increase the concentration of Ca2+ in the
plasma and lower that of
phosphate
But given therapeutically in a low intermittent dose, PTH and fragments of PTH paradoxically stimulate osteoblast activity and enhance bone formation.
What is calcitonin and what is its function?
Calcitonin is a peptide
hormone secreted by
the specialized ‘C’ cells
in the thyroid follicles.
The main action of calcitonin is on bone: • Inhibits osteoclasts • In the kidney: Decreases of the reabsorption of both Ca2+ and phosphate • Its overall effect: Decrease of the plasma Ca2+ concentration
What are the sources of vitamin D?
Two sources of vitamin D:
Dietary ergocalciferol (D2)
Cholecalciferol (D3) is generated in the skin by the action of ultraviolet irradiation.
What occurs in the conversion of cholecalciferol?
In the liver to calcifediol (25-hydroxy-vitamin D3)
Further in the kidney to calcitriol (1,25-
dihydroxy-vitamin D3) – the active form
What is the function of calcitriol?
Calcitriol
Stimulates the absorption of Ca2+ and phosphate
in the intestine
Mobilizes Ca2+ from bone
Increases Ca2+ reabsorption in the kidney
tubules
Promotes the maturation of osteoclasts and
stimulates their activity
Decreases collagen synthesis by osteoblasts
What function does estrogen have on bone metabolism?
• Inhibit the cytokines that
recruit osteoclasts
• Oppose the bone resorbing, Ca2+-
mobilizing action of PTH
• Increase osteoblast
proliferation and inhibit
apoptosis
• Withdrawal of estrogen, as happens at the menopause, can (and usually does) lead to osteoporosis.
How do glucocorticoids play a role in bone metabolism?
Glucocorticoids • Physiological concentrations are required for osteoblast differentiation.
• Excessive pharmacological concentrations: Inhibit osteoblast differentiation and activity Stimulate osteoclast action Result: Osteoporosis
What are some examples of bone diseases?
Rickets
osteoporosis
paget’s disease of bone
How are the drugs used in bone disorders classified?
1. Bisphosphonates а. I generation Clodronic acid b. II generation Alendronic acid Ibandronic acid Zoledronic acid
- Estrogens, SERM
Raloxifene - Parathormone analogs
Teriparatide - Monoclonal antibodies
against RANKL
Denosumab - Strontium
Strontium ranelate - Calcitonin
Calcitonin - Vit. D and analogs
Calcitriol
Cholecalciferol
Calcipotriol - Calcimimetics
Cinacalcet
What is the PK of bisphosphonates?
PK • Applied orally or i.v. • Poorly absorbed • Accumulate at the sites of bone mineralisation (50% of the dose) • Remain in bone potentially for months or years • The free drug is excreted unchanged by the kidney.
What is the PD of Bisphosphonates?
PD
• They inhibit bone resorption by
an action mainly on the
osteoclasts
• They form tight complexes with calcium in the bone matrix
• Osteoclasts are exposed to high concentrations of the drugs during bone resorption
What are the unwanted effects of bisphosphonates?
Unwanted effects • Oesophagitis (alendronate) • Bone pain – occasionally • Given intravenously – osteonecrosis of the jaw (zoledronate)
What are the clinical uses of bisphosphonates?
Clinical uses of bisphosphonates • Osteoporosis Prevention of fractures in high-risk individuals Alendronate – by mouth, daily or once weekly in addition to calcium with vitamin D3. Zoledronate – annually by intravenous infusion, expensive
• Malignant disease involving bone (e.g. metastatic breast cancer, multiple myeloma) To reduce bone damage, pain and hypercalcaemia
• Paget’s disease of bone
Intermittent administration
What is the mechanism of action, clinical use, and ADRs of Estrogens and SERM?
Raloxifene
Mechanism of action – SERM
• Agonist activity on bone, stimulating osteoblasts and
inhibiting osteoclasts
• Agonist actions on the cardiovascular system
• Antagonist activity on mammary tissue and the uterus
Clinical use
• An alternative to a bisphosphonate for secondary
prevention in postmenopausal women who cannot
tolerate a bisphosphonate
Adverse drug reactions
• Hot flushes, leg cramps, and peripheral edema
• Less common are thrombophlebitis and
thromboembolism
What are PTH and teriparatide?
Teriparatide – the peptide fragment (1- 34) of recombinant PTH: • Given in small doses subcutaneously once daily • Paradoxically stimulates osteoblast activity and enhances bone formation • Used to treat selected patients with osteoporosis • Well tolerated
What is the mechanism of action of Monoclonal antibodies against RANKL (Denosumab)?
Mechanism of action • Monoclonal antibody (IgG2 ), which targets and binds with high affinity with RANKL • Inhibits osteoclastogenesis and activity
What is the clinical use of Monoclonal antibodies against RANKL (Denosumab)?
Clinical use
• Treatment of postmenopausal
osteoporosis and some cancers
(prostate and breast)
What is the administration of Monoclonal antibodies against RANKL (Denosumab)?
Administration
• S.c. once every 6 months together
with Calcium and vitamin D
What is the ADR of Monoclonal antibodies against RANKL (Denosumab)?
ADR: • Infections (airways and urinary tract) because a number of cells in the immune system also express RANKL • Rarely – osteonecrosis of the jaw
What is strontium rantelate?
Strontium ranelate
• Inhibits bone resorption and also stimulates bone
formation
• An alternative to a bisphosphonate in prevention of
osteoporotic fractures, when a bisphosphonate is not
tolerated
• The precise mechanism of action is not clear
Strontium atoms are adsorbed onto the hydroxyapatite
crystals
Remain in the bone for many years
Eventually they exchange for calcium in the bone minerals
• The drug is well tolerated.
What are cholecalciferol and calcitriol used for?
Given orally
Deficiency states: prevention and treatment of
rickets and osteomalacia (cholecalciferol).
Osteodystrophy of chronic renal failure
(calcitriol).
What is calcipotriol used for?
Calcipotriol
Ointment
Psoriasis (inhibits cell proliferation; has effects
on immunologic markers that are thought to play
a role in the etiology of the disease)
What is calcitonin used for?
Synthetic salmon calcitonin
Given by subcutaneous or intramuscular
injection.
Clinical use:
• Hypercalcaemia (e.g. associated with neoplasia)
• Paget’s disease of bone (to relieve pain and
reduce neurological complications)
What is cinacalet?
A calcimimetic agent – mimics the action of
calcium in the body by:
• Mimics the stimulatory effect of Ca2+ on the calcium-sensing receptor to inhibit PTH secretion by the
parathyroid glands.
• The reduction in PTH levels also leads to a decrease
in blood calcium levels.
what are the clinical uses of cinalcet?
Clinical uses:
• In secondary hyperparathyroidism in patients with
serious kidney disease who need dialysis
• To reduce hypercalcemia in patients with
parathyroid carcinoma or with primary
hyperparathyroidism who cannot have their
parathyroid glands removed
Which are the hormones secreted by the thyroid gland?
- Thyroxine (T4)
- Tri-iodothyronine (T3)
- Calcitonin
Which hormone regulates hormone synthesis and secretion?
Hormone synthesis and secretion are regulated by thyroid-stimulating hormone (thyrotrophin) and influenced by plasma iodide.
What is the functional unit of the thyroid?
The functional unit of the thyroid is the follicle. The follicle: • A single layer of epithelial cells (1) • A cavity (*) filled with a thick colloid containing thyroglobulin.
How are thyroid hormones synthesized?
• Uptake of plasma iodide by the
follicle cells
• Oxidation of iodide and
iodination of tyrosine residues of
thyroglobulin to MIT and DIT
(thyroperoxidase)
• Coupling in pairs: either MIT with DIT to form T3, or two DIT
molecules to form T4.
• Endocytosis of the thyroglobulin
molecule into the follicle cell
• Proteolysis of thyroglobulin and releasing T4 and T3
• Secretion of T4 and T3
into the
plasma.
What are the actions of thyroid hormones?
Two categories:
• Affecting metabolism:
General increase in the metabolism of carbohydrates,
fats and proteins, T3 being three to five times more
active than T4
• Affecting growth and development – a critical
effect on growth:
Partly by a direct action on cells
Indirectly by influencing growth hormone production
and potentiating its effects on its target tissues
What is the mechanism of action of thyroid hormones?
Genomic actions – a
specific nuclear
receptor, TR
• T4 may be regarded as a prohormone, because when it enters the cell, it is converted to T3 • T3 then binds with high affinity to a member of the TR family • Activation of transcription, resulting in generation of mRNA and protein synthesis
Non-genomic actions
What are some abnormalities of thyroid function?
Hyperthyroidism
(thyrotoxicosis); either
diffuse toxic goiter or
toxic nodular goiter
Hypothyroidism; in
adults this causes
myxoedema, in infants
cretinism
Simple non-toxic goitre caused by dietary iodine deficiency, usually with normal thyroid function
Which are the drugs used for thyroid and thyroid activity?
- Drugs with the activity of thyroid hormones
Levothyroxine - Thyreostatic agents
Thiamazol Propylthiouracil - Iodides
Potassium iodide
What is levothyroxine?
Levothyroxine:
Synthetic compound
Given orally
Unwanted effects may occur with
overdose:
• Severe overdose:
Signs and symptoms of hyperthyroidism
Precipitating of angina pectoris, cardiac dysrhythmias
or even heart failure
• Less severe overdose
Increased bone resorption leading to osteoporosis
What is the action of thyreostatic agents? (Thiamzol, Propylthiouracil)
Mechanism of action:
• Inhibition of the iodination of tyrosil residues in thyroglobulin
• Inhibition of the thyroperoxidase-catalysed oxidation reactions
• Reduction of the deiodination of T4
to T3
in peripheral tissues (Propylthiouracil)
What is the clinical response of thyreostatic agents? (Thiamzol, Propylthiouracil)
The clinical response:
• After several weeks (the thyroid may have large stores of hormone)
• Propylthiouracil is thought to act somewhat more rapidly because of the
reduction of the deiodination of T4
to T3
What is the ADR of thyreostatic agents? (Thiamzol, Propylthiouracil)
Adverse drug reactions:
• Neutropenia and agranulocytosis (the most dangerous unwanted effect with an
incidence of about 1%, reversible on cessation of treatment}
• Rashes (more common up to 25%)
What are the indications of thyreostatic agents? (Thiamzol, Propylthiouracil)
Indications:
• Hyperthyroidism (diffuse toxic goitre) – long treatment (at least 1 year)
• In very severe hyperthyroidism (thyroid storm) – propylthiouracil is preferred.
The β-adrenoceptor antagonists (e.g. propranolol) are also used.
What is the mechanism of action of Potassium iodide?
Mechanism of action – not entirely clear:
• It may inhibit iodination of thyroglobulin, possibly by reducing
the H2O2 generation that is necessary for this process
What are the effects of potassium iodide?
Effects:
• Temporary inhibition of the release of thyroid hormones (10-14
days)
• Reduction in vascularity of the gland
What are the clinical uses of potassium iodide?
Clinical use:
• For the preparation of hyperthyroid subjects for surgical
resection of the gland
• As part of the treatment of thyroid storm
What are the ADRs of potassium iodide?
Adverse drug reactions (iodide in tears and saliva):
• Lacrimation, conjunctivitis
• Pain in the salivary glands
