Msk Week 3 Objective 11

Front 1

What type of drug is Denosumab and what is its MOA?

Back 1

Denosumab is a monoclonal antibody raised against the RANKL found on osteoclasts.
The mAb will bind to the RANKL and prevent the RANKL-RANK complex from forming. This would reduce osteoclast activity and therefore reduce bone resorption.
* Only in Phase III trials - not available*

Front 2

What results have been observed in the beginning trial stages of Denosumab treatment for osteoporosis?

Back 2

Within a couple hours of a 60g Denosumab injection, osteoclastogenesis stopped and bone resorption decreased.
Since injection good for 6 months.
Injections were accompanied by an increase in BMD in the lumbar spine, hip and distal third of radius.

Front 3

What are the two classifications for osteoporosis drugs?

Back 3

1) Anti-catabolic or anti-resorption
2) Anabolic

Front 4

Define osteoporosis?

Back 4

Decrease in bone density and strength because of an increase in bone resorption or a decrease in bone formation. BONE REMODELING IMBALANCE.

Front 5

What are some lifestyle changes that can be done to prevent osteoporosis?

Back 5

1) Supplementation – adequate calcium (1000-2000mg/day) and vitamin D3 (400-1000 IU)
2) Exercise – 30 minutes of weight bearing exercises, 3x a week, strength and balance
3) Normal, stable weight (BMI 22-25)
4) Fall Risk Reduction in home – OT to home, good lighting, nightlights, room clutter, throw rugs, etc
5) Check hearing and eyesight
6) Reduce EtOH consumption and smoking
7) Social support
8) Hip protectors

Front 6

How would you determine if a patient needs bone density scan?

Back 6

Has at least one major risk factor or 2 minor ones.

Front 7

Who to you provide osteoporosis treatment to? What criteria?

Back 7

1) High risk for fracture (i.e. elderly, women > men, low BMD)
2) Previous low trauma fracture

Front 8

What is the main goal of osteoporosis treatment and management?

Back 8

To prevent falls and future fractures, prevent further bone loss (resorption) and improve bone strength (formation).

Front 9

What are some drugs that cause drug-induced bone loss?

Back 9

1) Glucocorticoids (steroids)
2) Heparin
3) Excessive Vitamin A
4) Excessive Thyroid hormone
5) Aromatase inhibitors
6) Chemotherapy drugs
7) Anti-seizure meds
8) Anti-depressants (SSRIs)

Front 10

How does glucocorticoids cause bone loss?

Back 10

Increase bone resorption and decrease bone formation
- Inhibits osteoblast recruitment, maturation and action
- Decrease collagen formation
- Decrease Ca+ absorption from the gut by inhibiting vitamin D3
- Increases renal excretion of Ca+
- Increases PTH secretion
- Stimulates production of osteoclasts

Front 11

How can you minimize the detrimental effects of GC (inhaled and oral)?

Back 11

1) Use as low of dose as possible (<3mg)
2) Alternate day therapy
3) Increase supplementation
4) Anti-catabolic therapy (bisphosphonates) for those at high risk of fracture
5) Stop as soon as possible

Front 12

How much calcium and vitamin D3 should someone with osteoporosis and high risk of fracture be taking for management?

Back 12

1500mg of calcium and 800-2000 IU of vitamin D3.
Vitamin D3 must be activated by the liver and kidney therefore make sure to check liver and kidney function.

Front 13

How should the calcium supplements be taken?

Back 13

500mg at a time with food to increase the amount absorbed.
Important to take right before bed for overnight absorption, to help replace the bone resorption lost at night.
Use calcium citrate if history of kidney stones.

Front 14

How does calcium and vitamin D3 supplementation effect bone remodeling?

Back 14

- Vitamin D3 allows increased absorption of calcium from the gut
- Calcium slows the rate of bone loss and helps to increase bone density by being added to mineralized osteoid.

Front 15

What two hormones are used in ovarian hormone therapy (OHT)?

Back 15

Progesterone and estrogen.

Front 16

What is the MOA of estrogen in the treatment of osteoporosis?

Back 16

- It decreases bone resorption by inhibiting osteoclasts indirectly via the activation of OPG secretion from the osteoblasts. This prevents RANKL-RANK complex from forming and decreases osteoclast induction.
- Increases calcium absorption from the gut
- Increases IGF-1 and other growth hormones while decreasing cytokine production.

Front 17

What are the pros and cons of using estrogen OHT therapy for osteoporosis treatment?

Back 17

PROS
– decreased osteoporotic fractures and hip fractures therefore effective for preventing further fractures
- slows down bone loss
- decreased colorectal cancers
CONS
- increased thrombotic events
- increased strokes
- increased breast cancers
- increased MI

Front 18

What is the MOA of progesterone and how does it affect osteoporosis?

Back 18

- Increased osteoblast activity
- Stimulated osteoblast osteoid production
Progesterone stimulates bone formation and therefore slows down further bone density loss. It also reduces menopausal symptoms (hot flashes and night sweats). Further research is needed on fracture prevention.

Front 19

Who would you provide OHT therapy and why?

Back 19

1) A women in early menopause (<40yo)
2) Women with severe night sweats/menopausal symptoms
3) When other therapies aren’t working
*Note – cyclical therapy of progesterone has prevented bone loss in premenopausal women with abnormal cycles.
Make sure that the pros of OHT outweigh the risks therefore assess for cardiac, cerebrovascular and cancer risks before starting on OHT.

Front 20

What is the golden standard drug treatment(s) for osteoporosis?

Back 20

1) Bisphosphonates
2) OHT (or HRT)
3) SERMs

Front 21

What is the MOA of bisphosphonates in treatment of osteoporosis?

Back 21

ANTI-CATABOLIC, pyrophosphate analogue
- Bisphosphonates bind irreversibly to the hydroxyapatite crystals on the surface on the bone and are internalized by osteoclasts which disrupts their function.
- Bisphosphonates resist metabolic degradation via two mechanisms acting on the osteoclasts: i) reduce their ability to resorb bone ii) accelerate osteoclast apoptosis.
- Bisphosphonates decrease the solubility of the bone matrix therefore making it more resistant to bone resorption.

Front 22

What are the four oral bisphosphonates drugs available in Canada?

Back 22

1) Etidronate
2) Alendronate
3) Risedronate
4) Clodronate

Front 23

What are some of the IV bisphosphonates drugs available?

Back 23

1) Zoledronic acid
2) Pamidronate
3) Clodronate

Front 24

How should bisphosphonates be taken?

Back 24

Poorly absorbed therefore should be taken on an empty stomach with no food or drink for 60 minutes prior to taking the pill.
Bisphosphonates bind to Ca+2 and iron therefore wait 2 hours before taking these supplements

Front 25

What are some side effects of bisphosphonates?

Back 25

Usually well tolerated
Esophagitis with the nitrogen-containing bisphosphonate therefore take while standing and remain upright for 30 minutes afterwards – don’t take right before bed. Take with water.
Osteonecrosis of the jaw (rare) – occurs more often with IV therapy, check dental hygiene before giving.
Hypocalcemia – 2000U of Ca+2 and 800-1400 IU of vitamin D3 supplementation.

Front 26

What are the two non-nitrogen containing bisphosphonates and what benefit do they pose?

Back 26

Etidronate and Clodronate – don’t cause esophagitis

Front 27

What is special about the dosing schedule of etidronate?

Back 27

Inhibits osteoclasts and decreases mineralization therefore given cyclically; 400mg x14 consecutive days, every 3 months.
Can take lying down.
S/E of diarrhea

Front 28

What are the prevention and treatment doses for alendronate (Fosamax)?

Back 28

Prevention = 35mg once weekly
Treatment = 70mg once weekly

Front 29

How effective has alendronate been in preventing fractures and increasing BMD?

Back 29

- Shown to increase spinal bone density by almost 10% after 3 years
- Shown to reduce the frequency of fracture of vertebral, hip and wrist fractures by about 50%

Front 30

What is the MOA of calcitonin?

Back 30

ANTI-CATABOLIC nasal spray
- Directly inhibits osteoclasts by binding to a receptor on its surface; reducing bone resorption.
Analgesic effect – stronger narcotic then morphine without the addiction; used to manage pain from vertebral fractures.

Front 31

What effects has calcitonin had on preventing new fractures and BMD?

Back 31

- Proven to prevent new spinal fractures (33%) with very modest effect on spinal BMD. No evidence of preventing non-vertebral fractures was observed. Further research is needed.
- Used to treat postmenopausal osteoporosis but not approved for GC-induced osteoporosis

Front 32

What are the side effects of calcitonin?

Back 32

- Injection = tachypylaxis (rapidly decreasing response to a drug following administration on the initial dose)
- Nasal spray (200 IU/day) – usually well tolerated.

Front 33

What type of drug is Raloxifene?

Back 33

Selective estrogen receptor modulator – AKA SERM
ANTI-CATABOLIC

Front 34

What is the MOA of Raloxifene?

Back 34

Binds to estrogen receptors and produces different expression of estrogen-regulating genes in different tissues, activating some and inhibiting others.
Increases calcium absorption from the gut.

Front 35

What effect does SERMs (Raloxifene) have on preventing new fractures and increasing BMD?

Back 35

Mild increase in bone density
30% decrease in new vertebral fractures
No effect was observed on nonvertebral fractures
* Less effective at spinal fracture prevention than estrogen or bisphosphonates*

Front 36

What are some side effects of SERMs (Raloxifene)?

Back 36

Increased risk of thromboembolism (similar to estrogen)
Increased hot flashes and leg cramps
Neutral for CV disease and associated with reduced incidence of breast cancer and no increased in endometrial cancer

Front 37

When is Raloxifene use not recommended?

Back 37

In a women with breast cancer history
Past tamoxifen use.

Front 38

What type of drug is Teriparatide?

Back 38

- Recombinant 1-34 aa parathyroid horomone
- ANABOLIC

Front 39

How does PTH Teriparatide increase bone formation – MOA?

Back 39

- At intermittent levels PTH will stimulate bone formation
- Binds directly to the osteoblast and stimulate maturation and inhibits osteoblast apoptosis
- It also stimulates osteoclasts therefore paradoxically increasing resorption.

Front 40

What effect was PTH (Teriparatide) treatment shown to have on BMD and fracture prevention?

Back 40

- Spine BMD was shown to increase 2-3x more then that shown with anti-catabolic drugs, although decrease in BMD in the shaft of the radius in the first year (resorption of cortical bone?).
- Vertebral and non-vertebral fractures where reduced by 55-65% over 18-20 months in the Fracture prevention trial.

Front 41

What are the side effects/disadvantages of PTH (teriparatide) therapy?

Back 41

- Subcutaneous injection (20ug)
- Expensive ($20/day)
- Headache, dizziness, esophageal reflux, nausea
- Hypercalcemia
- Osteosarcoma

Front 42

Who can receive Teriparatide (PTH) therapy for osteoporosis?

Back 42

- Reserved for high risk patients due to the cost and the lack of both safety and efficacy data.
- Use limited to 2 years.

Front 43

What are the only two osteoporotic drugs that are anabolic (bone formation)?

Back 43

- PTH (Teriparatide)
- Progesterone

Front 44

Which drug, only available in Europe, both increases bone formation and decreases bone resorption?

Back 44

Strontium ranelate – ANABOLIC and ANTI-CATABOLIC
Reduced vertebral fractures by 6% (absolute)
Oral with no food avoidance
Side effects include diarrhea

Front 45

What osteoporotic drugs are anti-catabolic/anti-resorption

Back 45

1) Estrogen
2) Bisphosphonates
3) SERMs
4) Calcitonin

Front 46

Which combination therapies are effective for osteoporosis treatment?

Back 46

1) Estrogen + Progesterone
2) Estrogen + Progesterone + bisphosphonates
3) Estrogen + PTH
4) Calcium + vitamin D + all the above

Front 47

What combination therapies are NOT effective treatment options for osteoporosis?

Back 47

Bisphosphonates + PTH – but you can start with PTH, increase bone formation and stop it and start bisphosphonates to prevent the new bone formation from being lost.

Front 48

What % lifetime risk does a 60 year old man have of having an osteoporotic fracture?

Back 48

25% lifetime risk.

Front 49

What are some risk factors for osteoporosis in men (and women)?

Back 49

1) Smoking
2) Excess alcohol (>2 drinks/day)
3) Physical inactivity and decreased strength
4) Poor nutrition – calcium and vit D intake
5) Low androgen levels (hypogonadism or prostate cancer rx)
6) Low estrogen levels (thin)
7) Drug-induced (GC)

Front 50

How would you manage a man with osteoporosis?

Back 50

1) Vit D and calcium supplementation
2) Exercise program
3) Decrease drinking and smoking
4) Improve nutrition
5) Androgen therapy (testosterone) only if hypogonadism
6) Bisphosphonates
6) PTH in rare cases

Front 51

How would you treat a young woman with high risk factor for osteoporosis due to abnormal ovulation?

Back 51

1) First figure out why she is oligomenorrhea or amenorrhea (i.e. weight loss, excessive exercise, hormonal, stress) – provide emotional and social support
2) Increase calcium and vitamin D supplementation
3) Nutrition – balance energy, return weight to normal
4) Cyclic progesterone therapy
5) Avoid oral contraceptives – associated with lower BMD and bone loss.

Front 52

For a young women with an abnormal ovulation cycle, when would you prescribe progesterone (medroxyprogesterone or micronized progesterone)?

Back 52

During the days when she would physiologically normally have progesterone; Days 14-27 of her cycle.
300mg if progesterone, 10mg if medroxyprogesterone.

Front 53

Which bisphosphonates is covered by medicare?

Back 53

Etidronate

Front 54

In the 1994 study by J. Prior investigating the effects of cyclic progesterone on bone density, what did she find?

Back 54

Females on cyclic progesterone + calcium supplementation (1000mg) had increased bone mineral density compared to those on only progesterone, calcium or none.
Adding MPA increased BMD 2-3% in young females.

Front 55

What effect does oral contraceptives have on bone density?

Back 55

Shown to decrease BMD (statistically significant) in the spine and trochanter.

Front 56

Compare and contrast the absolute fracture risk reduction of alendronate, risedronate, OHT, Raloxifene (SERM) and Teriparatide (PTH)?

Back 56