Bone Disorders Flashcards
background on bone structure and composition (read only)
99% of the Calcium in our bodies is found in our
bones which serve as a reservoir for Ca2+ storage.
• 10% of total adult bone mass turns over each year
during remodeling process.
• During growth rate of bone formation exceeds
resorption and skeletal mass increases.
• Once adult bone mass is achieved equal rates of
formation and resorption maintain bone mass until
age of about 30 years when rate of resorption begins
to exceed formation and bone mass slowly
decreases.
3 types of bone cells (read only)
Osteoblasts: the differentiated bone forming cells
and secrete bone matrix on which Ca2+ and PO43-
precipitate.
• Osteocytes: the mature bone cells are enclosed in
bone matrix.
• Osteoclasts: a large multinucleated cell derived from
monocytes whose function is to resorb bone.
Inorganic bone is composed of hydroxyapatite and
organic matrix is composed primarily of collagen.
Calcium Metabolism (read only)
Ca is the most abundant mineral in the body.
• Ca salts in bone provide structural integrity of the skeleton.
• The amount of Ca is balanced among intake, storage, and excretion.
• This balance is controlled by transfer of Ca among 3 organs: intestine, bone, kidneys.
• Ca ions in extracellular and cellular fluids are essential to normal function of a host of biochemical processes
Turnover of Bone Minerals
read only
About 1000 mg of Ca is ingested per day.
• About 200 mg of this is absorbed into the body.
• Absorption occurs in the small intestine, and requires
vitamin D.
• The major site of Ca excretion in the body is the
kidneys.
• The rate of Ca loss and reabsorption at the kidney
can be regulated.
• Regulation of absorption, storage, and excretion of
Ca results in maintenance of calcium homeostasis.
• The plasma Ca concentration is regulated by PTH,
Vitamin D and calcitonin.
Phosphate Metabolism (read only)
P is an essential mineral necessary for ATP, cAMP
2nd messenger systems, and other roles.
• Phosphate absorption is an energy-requiring process
regulated by calcitriol.
• Phosphate deposition in bone, as hydroxyapatite,
depends on the plasma concentration of PTH, which,
with calcitriol, mobilizes both Ca2+ and phosphate
from the bone matrix.
• Phosphate is excreted by the kidney; here PTH
inhibits reabsorption and thus increases excretion
Osteoporosis
what is it?
The total bone mass of humans peaks at 25-35 years
of age.
• Men have more bone mass than women.
• A gradual decline occurs in both genders with aging,
but women undergo an accelerated loss of bone due
to increased resorption during menopause.
• Bone resorption exceeds formation.
• Reduced bone density and mass: osteoporosis
• Susceptibility to fracture.
• Earlier in life for women than men but eventually both
genders are affected
what are 2 types of agents that can treat osteoporosis?
- antiresorptive drugs
2. anabolic agents
how do antiresorptive drugs work?
decrease bone loss, e.g. bisphosphonates, calcitonin, selective estrogen receptor modulators (SERMs), denusomab , calcium
how do anabolic agents work?
which has both actions of antiresorptive and anabolic?
that increase bone formation, e.g. PTH, teriparatide .
•Strontium has both actions (antiresorptive and anabolic).
what can treat rickets and osteomalacia?
what can treat Paget’s disease
•Rickets and osteomalacia are treated with vitamin D
preparations.
•Paget’s disease is treated by bisphosphonates such as
pamidronate or zoledronate and calcitonin
Bisphosphonates (BPs)
name 2 types and common drugs of each
Aminobisphosphonates: (2 phosphates and an amino group)
alendronate, risedronate, pamidronate, zoledronate
Non-Aminobisphosphonates: etidronate,clodronate
Bisphosphonates (BPs)
main action?
what reduces their absorption
where are they eliminated?
Bisphosphonates (BPs) inhibit osteoclast activity through a variety of mechanisms.
- inhibit bone resorption
• BPs have very low oral bioavailability (~1%), and their
absorption is further reduced by food and by divalent
cations such as calcium. recommended that BPs be taken on an empty stomach, with plain
water.
• The BPs that are absorbed are highly bound to bone,
and are not metabolized. They are eliminated by the
kidney.
• The oral BPs are typically administered once weekly
Bisphosphonates (BPs)
how do aminobisphosphonates work?
Disrupt the mevalonate pathway, a pathway involved in the posttranslational modification of proteins that are involved in cellular signaling.
Disruption of the mevalonate pathway interrupts
osteoclast function and leads to apoptosis of the osteoclast
Bisphosphonates (BPs)
how do non-aminobisphosphonates work?
Increase the accumulation of cytotoxic metabolites within osteoclasts, interfering with their function and possibly leading to osteoclast cell death
Bisphosphonates (BPs)
Indications (8)
• Osteoporosis
• Paget’s disease of the bone (results in enlarged, deformed bones) - enlarged soft bone w/ less calcium
• Hypercalcemia:
• Malignancy
• Primary hyperparathyroidism (continuous parathyroid
hormone [PTH] release causes bone demineralization)
• Bone metastasis causing osteolysis:
• Multiple myeloma
• Bone metastases of malignant tumors
Bisphosphonates (BPs)
contraindications (2)
Hypocalcemia (low calc): BPs have exhibited decreases in serum calcium. It is recommended that deficiencies in calcium be addressed before initiation of therapy.
Poor renal function: BPs are eliminated renally
Bisphosphonates (BPs)
AE (4)
• Gastrointestinal: nausea, dyspepsia
• Esophagitis or esophageal erosion
• Osteonecrosis of the jaw with higher doses, jaw easily broken.
• Aminobisphosphonates also cause fever, flulike
symptoms are a transient, typically first-dose phenomenon seen with intravenous administration
Estrogens and Related Compounds
common drug name
MOA?
Raloxifene
- SERM, selective estrogen receptor modulators. It stimulates osteoblasts and inhibits osteoclasts
Estrogens and Related Compounds
Raloxifene
PK
- bioavailability?
- where is it concentrated?
It is well absorbed in the gastrointestinal tract, and
undergoes extensive first-pass metabolism (bioavailability 2%).
• Raloxifene is concentrated in tissues, and is converted to an active metabolite in liver, lungs, bone, spleen, uterus and kidney.
• Its half-life averages 32 h and excreted mainly in the feces.
Estrogens and Related Compounds
Raloxifene
AE (2) + alternative use?
Hot flushes, leg cramps, flu-like symptoms and peripheral oedema.
• Thrombophlebitis and thromboembolism.
• Raloxifene is not recommended for primary prevention of osteoporotic fractures, but is one alternative to a bisphosphonate postmenopausal women who cannot tolerate a bisphosphonate
Parathyroid Hormone (PTH)
structure?
common drug?
Parathyroid hormone, which consists of a single-chain
polypeptide of 84 amino acids
Teriparatide
Parathyroid Hormone (PTH)
MOA?
key effects?
receptor?
what does it stimulate?
PTH is released from the parathyroid gland. It regulates calcium and phosphate flux across cell membranes in bone and kidney
- Increased serum calcium
- Decreased serum phosphate
- Increased osteoclast activity in bone (indirect by increase RANKL activity
• PTH increases both resorption and formation but the net effect of excess PTH is resorption.
- actions largely mediated through the PTH-1 receptor. • anabolic effects are mediated by direct effects of PTH on osteoblasts, increasing their number and inhibiting their apoptosis.
- PTH also stimulates insulin-like growth factor (IGF-1) in osteoblasts, and IGF-1 also has anabolic effects on bone.
Parathyroid Hormone (PTH)
how is it admined?
duration of action?
indications? (1 main)
Teriparatide is administered as a subcutaneous injection once daily.
• It is both rapidly absorbed and rapidly eliminated, with plasma concentrations reaching their peak at 30 minutes post-injection and falling to undetectable levels after 3 hours.
Osteoporosis
• Severe osteoporosis and/or patients in whom previous therapies, including the BPs, have failed
• Osteoporosis secondary to corticosteroid use
Parathyroid Hormone (PTH)
contraindications? (6)
• Children or young adults with open epiphysis. (where bone is elongated)
• Hypercalcemia: PTH already raises Ca2+ levels.
• Active Paget’s disease of bone.
• Skeletal metastases or skeletal malignant conditions.
• History of radiation to the skeleton: risk of osteosarcoma
• Pregnancy and lactation: deleterious effects on fetal
bone development are possible
Parathyroid Hormone (PTH)
AE (4)
• Hypercalcemia (mild): PTH increases serum calcium.
• Leg cramps may occur.
• Nausea may occur.
• Orthostatic hypotension: PTH infusions have a
vasodilatory effect in animals
Vitamin D Replacement
what are the 2 major forms of vit d replacements?
what does it regulate generally?
common drugs
• The two major forms of vitamin D replacements are
vitamin D2 and vitamin D3.
• Vitamin D is an important regulator of calcium and
phosphate homeostasis and bone metabolism. It works
in conjunction with PTH
Vitamin D Replacement
common drugs
Calcitriol, ergocalciferol (vitamin D2), calcipotriene,
doxercalciferol, paricalcitol
Vitamin D Replacement
explain the vitamin d endocrine pathway
- Vit D3 formed by UV in skin goes to liver and gets converted to calcifediol (25(OH)D3)
- goes to kidney and becomes calcitriol (1,25)
- calcitriol enters blood and increases differentiation of osteoblasts and plays a role in calc and phos homeostasis
- calcitriol negative feedback on parathyroid hormone release
Vitamin D Replacement
action of drugs on vitamine D endocrine system?
exogenous ergocalciferol (vit D2)
alfacalcidol
exog calcifediol
exog calcitriol
- exogenous ergocalciferol (vit D2): formed in plants by UV is converted to D2 metabolits in liver and kidney (becomes Vit D3 in liver)
- alfacalcidol, exog calcifediol: increases formation of calcifediol in kidney to calcitriol
- exog calcitriol: increases blood calcium which negatively acts to inhibit parathyroid hormone release/activity
Vitamin D Replacement
How does in increase serum calcium?
• Increased calcium absorption from the intestine
• Regulation of bone resorption and formation
(This occurs via stimulation of both osteoblastic and osteoclastic processes. Osteoblasts form bone, and osteoclasts dissolve bone.)
• Increased calcium reabsorption in the distal renal tubules
• Vitamin D results in a negative feedback loop and
decreases transcription and secretion of PTH.
• Intracellularly, it binds vitamin D receptors (VDRs) and
binds DNA, where it regulates transcription of genes in
the intestine, bone, kidney, and parathyroid gland.
Vitamin D Replacement
dosage forms for calcitriol?
indications (4)
AE? (1 main)
- Calcitriol is available in oral and intravenous formulations. It is a lipid-soluble vitamin and therefore can accumulate and cause toxicity
- Osteoporosis
- Hyperparathyroidism
- Osteomalacia
- Rickets
Symptoms are primarily induced by hypercalcemia, which include GI pain, renal stones, and psychiatric disturbances.
RANKL Inhibitors
common drug? indication?
what is the pathway for triggering osteoclast diff and activation?
denosumab for osteoporosis
- osteoblast is stimulated to express a surface ligand, RANK ligand (RANKL) which reacts witha receptor on osteoclast called RANK (receptor activator of nuclear factor kapa B)
- this receptor causes diff and activation of osteoclast progenitors
- hbipohosphonates inhibit bone resorption by osteoclasts
- anti-RANKL antibodies (denos) bind RANKL and prevent the RANK-RANKL interaction
RANKL Inhibitors
MOA?
• RANKL (receptor activator of nuclear factor kappa
ligand) is a cytokine member of the TNF superfamily
• The binding of RANKL to RANK results in increased
bone resorption through the differentiation, activation,
and prolonged survival of osteoclasts.
• Denosumab is a new fully humanized monoclonal
antibody that binds RANKL and through binding causes
inhibition of RANKL and thus inhibits osteoclast activity.
RANKL Inhibitors
dosage form? half life long or short?
AE (4)
- Denosumab has a very long half-life and is administered once every 6 months via subcutaneous injection. The time to maximum concentration is 26 days
- Eczema (small increase in risk)
- Hypocalcemia
- Increased risk of infections (ie cellulitis)
- ONJ and atypical fractures
Calcitonin
common drug
MOA?
salcatonin (synthetic salmon calcitonin)
- It decreases the reabsorption of both calcium and
phosphate in the kidney - it inhibits bone resorption by binding to a specific receptor on osteoclasts, inhibiting their action.
Calcitonin
indication? (3)
• Hypercalcaemia (e.g. associated with neoplasia).
• Paget’ s disease of bone (to relieve pain and reduce
neurological complications) – but it is much less
convenient than an injected high potency
bisphosphonate.
• Postmenopausal and corticosteroid-induced
osteoporosis (with other agents
Calcitonin
dosage forms?
half life long or short?
• Calcitonin is given by subcutaneous or intramuscular
injection.
• Its plasma half-life is 4–12 min, but its action lasts for
several hours
Calcium Salts
common drugs (6 name salt)
uses?
calcium carbonate, calcium citrate, calcium phosphate,
calcium acetate, calcium gluconate and calcium lactate
each has their own use - calc carbonate has highest amount of elemental calc
Calcium and Vitamin D are essential nutrients for proper bone health.
• Vitamin D helps to increase the absorption of calcium, ultimately building stronger bones.
• It also improves the function of muscles, improving the balance and decreasing the likelihood of falls, which can lead to fractures
Calcium Salts intake levels (read only)
optimal intake varies by age
- About 1000 mg of Ca is ingested per day.
-About 200 mg of this is absorbed into the body.
-These levels of daily calcium may be found in diets which regularly
include large amounts of dairy products, canned fish with edible
bones, dark green vegetables, calcium-processed tofu, calcium
fortified orange juice, and other rich sources
Calcium Salts
AE?
• Oral calcium salts can cause gastrointestinal disturbance.
• Intravenous administration in emergency treatment of
hyperkalaemia requires care, especially in patients
receiving cardiac glycosides, the toxicity of which is
influenced by extracellular calcium ion concentration
