Bone Disorders

Question 1

background on bone structure and composition (read only)

Answer 1

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.

Question 2

3 types of bone cells (read only)

Answer 2

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.

Question 3

Calcium Metabolism (read only)

Answer 3

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

Question 4

Turnover of Bone Minerals

read only

Answer 4

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.

Question 5

Phosphate Metabolism (read only)

Answer 5

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

Question 6

Osteoporosis

what is it?

Answer 6

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

Question 7

what are 2 types of agents that can treat osteoporosis?

Answer 7

1. antiresorptive drugs

2. anabolic agents

Question 8

how do antiresorptive drugs work?

Answer 8

decrease bone loss, e.g. bisphosphonates, calcitonin, selective estrogen receptor modulators (SERMs), denusomab , calcium

Question 9

how do anabolic agents work?

which has both actions of antiresorptive and anabolic?

Answer 9

that increase bone formation, e.g. PTH, teriparatide .

•Strontium has both actions (antiresorptive and anabolic).

Question 10

what can treat rickets and osteomalacia?

what can treat Paget’s disease

Answer 10

•Rickets and osteomalacia are treated with vitamin D
preparations.
•Paget’s disease is treated by bisphosphonates such as
pamidronate or zoledronate and calcitonin

Question 11

Bisphosphonates (BPs)

name 2 types and common drugs of each

Answer 11

Aminobisphosphonates: (2 phosphates and an amino group)
alendronate, risedronate, pamidronate, zoledronate

Non-Aminobisphosphonates: etidronate,clodronate

Question 12

Bisphosphonates (BPs)

main action?
what reduces their absorption
where are they eliminated?

Answer 12

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

Question 13

Bisphosphonates (BPs)

how do aminobisphosphonates work?

Answer 13

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

Question 14

Bisphosphonates (BPs)

how do non-aminobisphosphonates work?

Answer 14

Increase the accumulation of cytotoxic metabolites within osteoclasts, interfering with their function and possibly leading to osteoclast cell death

Question 15

Bisphosphonates (BPs)

Indications (8)

Answer 15

• 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

Question 16

Bisphosphonates (BPs)

contraindications (2)

Answer 16

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

Question 17

Bisphosphonates (BPs)

AE (4)

Answer 17

• 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

Question 18

Estrogens and Related Compounds

common drug name
MOA?

Answer 18

Raloxifene

- SERM, selective estrogen receptor modulators. It stimulates osteoblasts and inhibits osteoclasts

Question 19

Estrogens and Related Compounds

Raloxifene
PK
- bioavailability?
- where is it concentrated?

Answer 19

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.

Question 20

Estrogens and Related Compounds

Raloxifene
AE (2) + alternative use?

Answer 20

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

Question 21

Parathyroid Hormone (PTH)

structure?
common drug?

Answer 21

Parathyroid hormone, which consists of a single-chain
polypeptide of 84 amino acids

Teriparatide

Question 22

Parathyroid Hormone (PTH)

MOA?
key effects?
receptor?
what does it stimulate?

Answer 22

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.

Question 23

Parathyroid Hormone (PTH)

how is it admined?
duration of action?

indications? (1 main)

Answer 23

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

Question 24

Parathyroid Hormone (PTH)

contraindications? (6)

Answer 24

• 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

Question 25

Parathyroid Hormone (PTH) AE (4)

Answer 25

• Hypercalcemia (mild): PTH increases serum calcium. • Leg cramps may occur. • Nausea may occur. • Orthostatic hypotension: PTH infusions have a vasodilatory effect in animals

Question 26

Vitamin D Replacement what are the 2 major forms of vit d replacements? what does it regulate generally? common drugs

Answer 26

• 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

Question 27

Vitamin D Replacement common drugs

Answer 27

Calcitriol, ergocalciferol (vitamin D2), calcipotriene, | doxercalciferol, paricalcitol

Question 28

Vitamin D Replacement explain the vitamin d endocrine pathway

Answer 28

- 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

Question 29

Vitamin D Replacement action of drugs on vitamine D endocrine system? exogenous ergocalciferol (vit D2) alfacalcidol exog calcifediol exog calcitriol

Answer 29

- 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

Question 30

Vitamin D Replacement How does in increase serum calcium?

Answer 30

• 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.

Question 31

Vitamin D Replacement dosage forms for calcitriol? indications (4) AE? (1 main)

Answer 31

- 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.

Question 32

RANKL Inhibitors common drug? indication? what is the pathway for triggering osteoclast diff and activation?

Answer 32

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

Question 33

RANKL Inhibitors | MOA?

Answer 33

• 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.

Question 34

RANKL Inhibitors dosage form? half life long or short? AE (4)

Answer 34

- 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

Question 35

Calcitonin common drug MOA?

Answer 35

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.

Question 36

Calcitonin indication? (3)

Answer 36

• 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

Question 37

Calcitonin dosage forms? half life long or short?

Answer 37

• Calcitonin is given by subcutaneous or intramuscular injection. • Its plasma half-life is 4–12 min, but its action lasts for several hours

Question 38

Calcium Salts common drugs (6 name salt) uses?

Answer 38

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

Question 39

``` Calcium Salts intake levels (read only) ```

Answer 39

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

Question 40

Calcium Salts | AE?

Answer 40

• 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