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Powerpoint Templates
Page 1
Bisphosphonates
Powerpoint Templates
Page 2
Bisphosphonates are
pyrophosphate
analogues inwhich
the oxygen in p–o–p
has been replaced by
a carbon, resulting in
a metabolically stable
p–c–p structure
Resistant to
enzymatic destruction
Powerpoint Templates
Page 3
Bisphosphonates have two side chains:
R1 affects binding affinity tobone;
R2 affects antiresorptive capacity and,
possibly,
Side-effect profile.
Bisphosphonates vary in potency
Based on these specific side chains.
Powerpoint Templates
Page 4
.
Powerpoint Templates
Page 5
Generations of Bisphosphonates
• With each successive generation, there has been
increased potency, with more selectivity for inhibition
of resorption and less inhibition of bone formation.
• First-generation bisphosphonates, such as etidronate
and clodronate, inhibit bone formation and bone
resorption equally.
• Second-generation bisphosphonates include
pamidronate and alendronate
• The third generation includes the highly potent
risedronate and zolendronate.
Powerpoint Templates
Page 6
Mechanism of action
• Nitrogenous bisphosphonates act on bone
metabolism by binding and blocking the
enzyme farnesyl diphosphate synthase
(FPPS) in the HMG-coa reductase
pathway (also known as the mevalonate
pathway)
Powerpoint Templates
Page 7
Powerpoint Templates
Page 8
• Disruption of the HMG coa-reductase
pathway at the level of FPPS prevents the
formation of two metabolites (farnesol and
geranylgeraniol) that are essential for
connecting some small proteins to the cell
membrane. This phenomenon is known as
prenylation, and is important for proper
sub-cellular protein trafficking
Powerpoint Templates
Page 9
• While inhibition proteins can affect
osteoclastogenesis, cell survival, and
cytoskeletal dynamics. In particular, the
cytoskeleton is vital for maintaining the
"ruffled border" that is required for contact
between a resorbing osteoclast and a
bone surface.
Powerpoint Templates
Page 10
Non-N-containing bisphosphonates
• Etidronate ,Clodronate ,Tiludronate
• The non-nitrogenous bisphosphonates
(disphosphonates) are metabolised in the
cell to compounds that replace the
terminal pyrophosphate of ATP, forming a
nonfunctional molecule that competes with
ATP in the cellular energy metabolism.
The osteoclast initiates apoptosis and
dies, leading to an overall decrease in the
breakdown of bone
Powerpoint Templates
Page 11
Pharmacokinetics
• Oral bisphosphonates have a very low
bioavailability and poor gastrointestinal
absorption rates (from <0.7% alendronate
and risedronate to 6% for etidronate).
• Oral absorption can be diminished in the
presence of mineral water, other liquids,or
food in the stomach.
• Absorbed bisphosphonate remains in the
skeleton for prolonged periods(half-lives of
1.5 to 10 years), whereas nonincorporated
drug is excreted in the urine
Powerpoint Templates
Page 12
Indications for Use
• Indications for bisphosphonates include such conditions
1. Postmenopausal
2. Glucocorticoid-induced osteoporosis,
3. Paget’s disease,
4. Osteolytic and osteoblastic bone metastases,
5. Fibrous dysplasia,
6. Heterotopic ossification,
7. Myositis ossificans.
8. Other bisphosphonates, medronate (R1, R2 = H) and
oxidronate (R1 = H, R2 = OH) are mixed with radioactive
technetium and are injected for imaging bone and
detecting bone disease
Powerpoint Templates
Page 13
Powerpoint Templates
Page 14
Fracture Intervention Trial
• Here 658 osteoporotic women with either
vertebral fracture or osteoporosis at
femoral neck were treated with
alendronate for 3 to 4 Years.
• There was decreased risk of fracture, with
relative risks of 0.47 for hip fracture , 0.52
for radiographic vertebral fracture, 0.55 for
clinical vertebral fracture, and 0.70 for all
clinical fractures
Powerpoint Templates
Page 15
• An oral daily dose of risedronate (5 mg)
resulted in BMD increases after 6 months
of therapy.
• At 24 months, lumbar spine BMD
increased from baseline by 4%, with
increases of 1.3% and 2.7% in the femoral
neck and femoral trochanter, respectively
• A single weekly dose is as clinically
effective as daily dosage but with lower
incidences of dyspepsia,Esophagitis, and
gastroesophageal reflux disease (GERD)
Powerpoint Templates
Page 16
• Thirteen patients who received 30 mg of
pamidronate intravenously over 3 months
had an increased BMD of 6.2% in the
lumbar spine and 4.7% in the hip.
• Parenteral zolendronate administered at
annual intervals showed 4.3% to 5.1%
increase in BMD in the treatment group
for spine than in the placebo group
Powerpoint Templates
Page 17
Bisphosphonates in Metastatic disease
1. They control hypercalcemia,
2. Reduce bone pain,
3. Delay skeletally related events (sres),
4. Reduce the number of pathologic
fractures,
5. Prolong survival.
Powerpoint Templates
Page 18
• Intrvenous zolendronate and
palmindronate are the ones most useful
and should be combined with either
chemotherapy or hormonal therapy in
women with metastatic bone disease.
• Zolendronate is the first bisphosphonate
shown to be effective in both lytic and
blastic metastatic disease
Powerpoint Templates
Page 19
• Studies suggest the use of bisphosphonates
As oral and local adjuvants in total joint
arthroplasties increase periimplant bone
density or reduce implant migration
• The effect of soaking morselized allograft in
bisphosphonate before impacting it around
an experimental implant has been described
Powerpoint Templates
Page 20
Drug Interactions
• Bisphosphonates generally should not be taken
with antacids that contain aluminum or
magnesium, bottled water containing minerals,
or calcium supplements because these agents
decrease bisphosphonate absorption.
• Food renders bisphosphonates ineffective;
• A 2-hour interval between meals drug is
recommended.
• Aminoglycosides taken with bisphosphonates
may cause severe hypocalcemia.
Powerpoint Templates
Page 21
Adverse effects
• Oral bisphosphonates causes
Gastrointestinal complications such as
gastritis or esophagitis, abdominal pain,
nausea, vomiting, diarrhea, and constipation.
• To minimize gastrointestinal inflammation
• And ulcer, patients should remain upright
(sitting or standing) for at least 30 minutes
after taking the medication
Powerpoint Templates
Page 22
BISPHOSPHONATE-RELATED
OSTEONECROSIS OF THE JAW
• AKA Phossy jaw
• American Academy of Oral and Maxillofacial
Surgeons (AAOMS) proposed a definition for
bisphosphonate-related ONJ that requires the
satisfaction of the following criteria:
• (1) Current or prior use of bisphosphonate
• (2) An area of exposed bone within the maxillofacial
region without healing for more than 8 weeks
• (3) Absence of history of radiation to the jaws
Powerpoint Templates
Page 23
• It has been postulated that reduced bone
remodeling associated with bisphosphonate
use may lead to an increased risk of
developing bone necrosis in select patients.
• The antiangiogenic effects of
bisphosphonates may result in a reduction in
the blood supply to the region and contribute
to poor wound healing.
• Infection has also been implicated in the
pathogenesis of ONJ
Powerpoint Templates
Page 24
STAGES
• stage 1-were patients with asymptomatic
necrotic bone
• stage 2-accompanied by infection with or
without purulent drainage
• stage 3- patients with necrotic bone
accompanied by infection, pain, and at least
one of the conditions, including pathologic
fractures, extraoral fistula, or osteolysis
extending to the inferior border
Powerpoint Templates
Page 25
ATYPICAL SUBTROCHANTERIC AND
DIAPHYSEAL FRACTURES
• bisphosphonate may alter the biomechanical
properties of bone matrix via its effect on bone
collagen and bone mineralization density
distribution, resulting in brittle and stiff bones
that could fracture with littletrauma.
• Reduced bone remodeling, coupled with the
antiangiogenic effect of bisphosphonates, may
further impair the healing of stress fractures,
which eventually develop into a complete
fracture.
Powerpoint Templates
Page 26
Powerpoint Templates
Page 27

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Bisphosphonates

  • 2. Powerpoint Templates Page 2 Bisphosphonates are pyrophosphate analogues inwhich the oxygen in p–o–p has been replaced by a carbon, resulting in a metabolically stable p–c–p structure Resistant to enzymatic destruction
  • 3. Powerpoint Templates Page 3 Bisphosphonates have two side chains: R1 affects binding affinity tobone; R2 affects antiresorptive capacity and, possibly, Side-effect profile. Bisphosphonates vary in potency Based on these specific side chains.
  • 5. Powerpoint Templates Page 5 Generations of Bisphosphonates • With each successive generation, there has been increased potency, with more selectivity for inhibition of resorption and less inhibition of bone formation. • First-generation bisphosphonates, such as etidronate and clodronate, inhibit bone formation and bone resorption equally. • Second-generation bisphosphonates include pamidronate and alendronate • The third generation includes the highly potent risedronate and zolendronate.
  • 6. Powerpoint Templates Page 6 Mechanism of action • Nitrogenous bisphosphonates act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate synthase (FPPS) in the HMG-coa reductase pathway (also known as the mevalonate pathway)
  • 8. Powerpoint Templates Page 8 • Disruption of the HMG coa-reductase pathway at the level of FPPS prevents the formation of two metabolites (farnesol and geranylgeraniol) that are essential for connecting some small proteins to the cell membrane. This phenomenon is known as prenylation, and is important for proper sub-cellular protein trafficking
  • 9. Powerpoint Templates Page 9 • While inhibition proteins can affect osteoclastogenesis, cell survival, and cytoskeletal dynamics. In particular, the cytoskeleton is vital for maintaining the "ruffled border" that is required for contact between a resorbing osteoclast and a bone surface.
  • 10. Powerpoint Templates Page 10 Non-N-containing bisphosphonates • Etidronate ,Clodronate ,Tiludronate • The non-nitrogenous bisphosphonates (disphosphonates) are metabolised in the cell to compounds that replace the terminal pyrophosphate of ATP, forming a nonfunctional molecule that competes with ATP in the cellular energy metabolism. The osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone
  • 11. Powerpoint Templates Page 11 Pharmacokinetics • Oral bisphosphonates have a very low bioavailability and poor gastrointestinal absorption rates (from <0.7% alendronate and risedronate to 6% for etidronate). • Oral absorption can be diminished in the presence of mineral water, other liquids,or food in the stomach. • Absorbed bisphosphonate remains in the skeleton for prolonged periods(half-lives of 1.5 to 10 years), whereas nonincorporated drug is excreted in the urine
  • 12. Powerpoint Templates Page 12 Indications for Use • Indications for bisphosphonates include such conditions 1. Postmenopausal 2. Glucocorticoid-induced osteoporosis, 3. Paget’s disease, 4. Osteolytic and osteoblastic bone metastases, 5. Fibrous dysplasia, 6. Heterotopic ossification, 7. Myositis ossificans. 8. Other bisphosphonates, medronate (R1, R2 = H) and oxidronate (R1 = H, R2 = OH) are mixed with radioactive technetium and are injected for imaging bone and detecting bone disease
  • 14. Powerpoint Templates Page 14 Fracture Intervention Trial • Here 658 osteoporotic women with either vertebral fracture or osteoporosis at femoral neck were treated with alendronate for 3 to 4 Years. • There was decreased risk of fracture, with relative risks of 0.47 for hip fracture , 0.52 for radiographic vertebral fracture, 0.55 for clinical vertebral fracture, and 0.70 for all clinical fractures
  • 15. Powerpoint Templates Page 15 • An oral daily dose of risedronate (5 mg) resulted in BMD increases after 6 months of therapy. • At 24 months, lumbar spine BMD increased from baseline by 4%, with increases of 1.3% and 2.7% in the femoral neck and femoral trochanter, respectively • A single weekly dose is as clinically effective as daily dosage but with lower incidences of dyspepsia,Esophagitis, and gastroesophageal reflux disease (GERD)
  • 16. Powerpoint Templates Page 16 • Thirteen patients who received 30 mg of pamidronate intravenously over 3 months had an increased BMD of 6.2% in the lumbar spine and 4.7% in the hip. • Parenteral zolendronate administered at annual intervals showed 4.3% to 5.1% increase in BMD in the treatment group for spine than in the placebo group
  • 17. Powerpoint Templates Page 17 Bisphosphonates in Metastatic disease 1. They control hypercalcemia, 2. Reduce bone pain, 3. Delay skeletally related events (sres), 4. Reduce the number of pathologic fractures, 5. Prolong survival.
  • 18. Powerpoint Templates Page 18 • Intrvenous zolendronate and palmindronate are the ones most useful and should be combined with either chemotherapy or hormonal therapy in women with metastatic bone disease. • Zolendronate is the first bisphosphonate shown to be effective in both lytic and blastic metastatic disease
  • 19. Powerpoint Templates Page 19 • Studies suggest the use of bisphosphonates As oral and local adjuvants in total joint arthroplasties increase periimplant bone density or reduce implant migration • The effect of soaking morselized allograft in bisphosphonate before impacting it around an experimental implant has been described
  • 20. Powerpoint Templates Page 20 Drug Interactions • Bisphosphonates generally should not be taken with antacids that contain aluminum or magnesium, bottled water containing minerals, or calcium supplements because these agents decrease bisphosphonate absorption. • Food renders bisphosphonates ineffective; • A 2-hour interval between meals drug is recommended. • Aminoglycosides taken with bisphosphonates may cause severe hypocalcemia.
  • 21. Powerpoint Templates Page 21 Adverse effects • Oral bisphosphonates causes Gastrointestinal complications such as gastritis or esophagitis, abdominal pain, nausea, vomiting, diarrhea, and constipation. • To minimize gastrointestinal inflammation • And ulcer, patients should remain upright (sitting or standing) for at least 30 minutes after taking the medication
  • 22. Powerpoint Templates Page 22 BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW • AKA Phossy jaw • American Academy of Oral and Maxillofacial Surgeons (AAOMS) proposed a definition for bisphosphonate-related ONJ that requires the satisfaction of the following criteria: • (1) Current or prior use of bisphosphonate • (2) An area of exposed bone within the maxillofacial region without healing for more than 8 weeks • (3) Absence of history of radiation to the jaws
  • 23. Powerpoint Templates Page 23 • It has been postulated that reduced bone remodeling associated with bisphosphonate use may lead to an increased risk of developing bone necrosis in select patients. • The antiangiogenic effects of bisphosphonates may result in a reduction in the blood supply to the region and contribute to poor wound healing. • Infection has also been implicated in the pathogenesis of ONJ
  • 24. Powerpoint Templates Page 24 STAGES • stage 1-were patients with asymptomatic necrotic bone • stage 2-accompanied by infection with or without purulent drainage • stage 3- patients with necrotic bone accompanied by infection, pain, and at least one of the conditions, including pathologic fractures, extraoral fistula, or osteolysis extending to the inferior border
  • 25. Powerpoint Templates Page 25 ATYPICAL SUBTROCHANTERIC AND DIAPHYSEAL FRACTURES • bisphosphonate may alter the biomechanical properties of bone matrix via its effect on bone collagen and bone mineralization density distribution, resulting in brittle and stiff bones that could fracture with littletrauma. • Reduced bone remodeling, coupled with the antiangiogenic effect of bisphosphonates, may further impair the healing of stress fractures, which eventually develop into a complete fracture.