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Terms in this set (71)
What are 5 types of anti-resorptive drugs?
1) Hormone replacement therapy
2) Raloxifene (Evista)
4) Calcitonin (Calcimar)
5) Denosumab (Prolia
Name an anabolic drug for the treatment of osteoporosis (and brand name)
Name 4 bisphosphonates (and brand names)
1) Etidronate (Didrocal)
2) Alendronate (Fosamax)
3) Rsedronate (Actonel)
4) Zoledronate (Aclasta)
What is the effect of anti-resorptive drugs on bone remodelling (on BMU activity)?
- Affects marrow precursor pool to decreases BMU ACTIVATION;
- Improves bond remodeling BALANCE by preventing bone resorption
Why are anti-resorptive drugs' effect on BMU transient?
- new BMU activity is suppressed, but old BMUs already initiated will continue to refill resorbed sites
- but BMU activity is coupled, so decreasing osteoclast activity will also decrease osteoblast activity in the long-term
What 3 mechanisms of anti-resorptive drugs are responsible for increasing BMD?
1) Refilling remodling space
2) Increase mineralization
3) Positive remodeling balance
What type of bone is more affected by anti-resorptive drugs in terms of increasing BMD? why?
Trabecular bone, because they are more prone to remodel.
What accounts for the majority (70-97%) of the effect of anti-resorptive drugs on decreasing fractures?
Preventing micoarchitectural damage to PRESERVE ARCHITECTURE
What are the 3 effects of anabolic drugs in treatment of osteoporosis?
1) Increase activation frequency (increase number of BMUs)
2) Increase amount of bone formed by each BMU (due to stimulation of osteoblast activity)
3) May stimulate osteoblast activity directly, WITHOUT preceding resorption phase (conversion of lining cells to osteoblasts)
How effect do anabolic drugs have on bone architecture?
IMPROVES archecture (by repairing damage, and renewing trabecular remodeling)
What did the WHI trials demonstrate regarding HRT and osteoporosis?
1) Estrogen/progestins reduced risk of fractures in postmenopausal women
2) BUT long term benefits did not outweigh the risks
What is the WHI recommendation on duration of use of HRT?
less than 5 years
What category of drugs does raloxifene belong to? What specific thing does it NOT cause?
Selective Estrogen Receptor Modifier (SERM).
Does not cause endometrial stimulation
Raloxifene has been shown to reduce the risk of what type of fracture by 50%? What does it not reduce the risk of?
Risk of vertebral fracture.
Does not reduce risk of non-vertebral or hip fractures
What are the adverse effects of raloxifene?
- aggravation of vasomotor symptoms (esp. in recent postmenopausal)
- increase risk of venous thrombosis
What part of the bisphosphonate molecule is essential for binding to hydroxyapatite and biological activity?
The P-C-P group (acts as 'bone hook')
What part of the bisphoshonate molecule determines potency?
the R2 group
What is the R2 group for etidronate?
What is the R2 group for Alendronate?
What is the R2 group for Pamidronate?
How can hydroxyapatite binding be enhanced in bisphosphonates?
If R1 is an OH group
What is the MOA of bisphosphonates?
1) Incorporates into bone, then released when hydroxyapatite dissolved by osteoclast acid production
2) IEndocytosed by osteoclasts, where it impairs recruitment, differentiation and activity of osteoclasts, and increase apoptosis
3) results in reduction in activation of new BMU, thus decrease bone turnover
What is the problem with the dose of etidronate that can inhibit bone resorption?
Can also impair bone mineralization
What can result if etidronate is used alone continuously?
Accumulation of unmineralzied osteoid (osteomalacia)
How do you avoid osteomalacia with use of etidronate?
Give it cyclically - 14 days of etidroante 400mg/day, followed by 76 days of calcium carbonate 500mg/day
Due to the efficacy of etidronate, what should it be used for?
Secondary prevention in post-menopausal women (T-score </=-2.0 or previous fracture)
In secondary prevention, what is the efficacy of etidronate? (What is the absolute risk reduction?)
Decreased risk of vertebral fracture by ~50% (ARR=5%)
What are 2 advantages of 2nd and 3rd generation bisphosphonates over etidronate?
- Inhibit bone resorption at doses that do not affect bone mineralization
- reduce risk of hip, vertebral and non-vertebral fractures in secondary prevention
Which bisphosphonate also decreases risk of vertebral fracture in primary prevention?
What is the oral absorption of alendronate and risedronate?
What is the plasma half-life of alendronate and risedonate?
How are alendronate and risedonate excreted?
~50% by kidney
What is the half-life of alendronate and risedonate in bone?
> 10 years
What is the dose/regimen of alendronate?
What is the dose/regimen for risedronate?
5mg daily, OR
35mg weekly, OR
75mg/day X 2 consecutive days/month
What is the dose/regimen for zoledronate?
5mg once/year IV infusion
What are the most common SE for oral bisphosphonates?
- Abdominal pain
- Nausea and vomiting
What are the most common SE for zoledronate?
Transient flu-like symptoms on injection
What is a common SE of alendronate and risedronate? How may it be avoided?
take in upright position with full glass of water;
remain upright for further 30 min
What are 3 serious adverse effects for all bisphosphonates?
1) Osteonecrosis of the jaw
2) Atypical femur fracture
3) Esophageal cancer
What is osteonecrosis of the jaw
Exposed necrotic bone in the jaw region, not healing after 6-8 weeks
What are most cases of osteonecrosis of the jaw associated with?
- IV administration of high doses for > 2years in cancer patients
- most after dental extraction
Risk of atypical femur increases with ______________, and decreases on ___________
increasing duration of use;
The increase in absolute risk of atypical femur fracture with use of bisphosphonate is what?
5 cases per 10 000 patient years
Long term therapy with bisphosphonates prolongs suppression of bone turnover, which can DIRECTLY cause what 3 things?
1) Increase mineralization
2) Accumulation of microdamage
3) Inability to heal
What can accumulation of microdamage lead to?
increase risk of fractures
What can increased mineralization and accumulation of microdamage lead to?
increased brittleness of bone
Esphoageal cancer risk may increase in which patients?
older patients with =/> 10 prescriptions in 5 years
In post-menopausal women, the anti-fracture efficacy of bisphosphonates has been shown for how long?
Discontinuation of bisphosphonates at 5 years is associated with what in post-menopausal women?
Increased risk of vertebral fractures
What are 4 other uses of bisphosphonates? (other than post-menopausal osteoporosis)
1) Increase BMD in men with osteoporosis
2) Prevention and treatment of glucocorticoid-induced osteoporosis
3) Paget's disease of bone in men and women
4) Treatment of bone metastases of various types of cancer (reduce bone pain and risk of fractures)
How do bone cancer cells stimulate tumor growth?
- Express growth factors (PTHrP)
- PTHrP induce osteoblasts to increase production of RANKL and formation of osteoclast
- osteoclast release growth factors and Ca2+ form bone which stimulates tumor growth
What is the role of calcitonin in the body?
To decrease plasma calcium (help maintain homeostasis of calcium)
What is the MOA of calcitonin?
Suppresses the activity of osteoclasts (decreases bone resorption)
What specific fractures does calcitonin reduce the risk of? by how much?
Reduce vertebral fractures by ~30%
What are the ADR of calcitonin?
1) Local irritation and nose bleeds (intranasal route)
2) long-term use assoc. with small increase in cancer risk
What is the place in therapy of intranasal calcitonin in post-menopausal osteoporosis?
What are 2 other uses of calcitonin?
- pain assoicated with acute vertebral fractures
- injectable approved for Paget's disease and severe hypercalcemia
What is the MOA of denosumab?
Monoclonal antibody to RANKL, and mimics action of osteoprotegerin (OPG):
- binds RANKL to prevent its binding to RANK receptor
- results in decrease in osteoclast formation
What are the 4 ADR of denosumab?
1) Hypocalcemia (2%)
2) Serious infections including cellulitis (interfere with immune cells)
4) Osteonecrosis of jaw in higher doses
What is the efficacy of denosumab in reducing fractures?
- Reduce vertebral by 60%
- Reduce non-vertebral by 20%
- Reduce hip by 40%
(in women with T-score < -2.5; thus secondary prevention)
What type of conditions may denosumab be useful for?
- temporary rapid bone resorption (eg. aromatase inhibitor treatment)
What is the dose/regimen for denosumab?
- 60mg SC q6months
What does teriparatide resemble physically?
The 34 n-terminal aa sequence of human PTH
What is the MOA of teriparatide for increasing BMD?
- increase recruitment and differentiation of osteoblasts
- decreasing apoptosis of osteoblast
How long is the "anabolic window" of teriparatide? What happens after this?
- 12-18 months
- subsequent stimulation of bone resorption (b/c also stimulates osteoclast differentiation)
What is the efficacy of teriparatide?
- decrease vertebral fracture by 65%
- decrease non-vertebral by 53%
(for secondary prevention in post-menopausal women)
What might be an ADR of teriparatide?
hypercalcemia and/or hypercalciuria
What are the limitations of teriparatide?
Treatment duration limited to 2 years
- bone density increase will be lost on D/C, unless followed with anti-resorbing agent
What are 2 uses of teriparatide?
1) Severe osteoporosis in post-menopausal women
2) Glucocorticoid-induced osteoporosis in high-risk patients
What is the regimen of teriparatide?
SC once daily
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