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IN
MANAGEMENT OF OSTEOPOROSIS
DR. RABI NARAYAN SATAPATHY
ASST.PROFESSOR
DEPT. OF OBST.& GYNAECOLOGY
SCB MEDICAL COLLEGE, C...
OSTEOPOROSIS NOW A GLOBAL PROBLEM
AGE
B
M
D
30 – 35
PROGRESSIVE CHANGE IN BMD WITH AGE
N
D
CHANGES IN BONE DENSITY WITH AGE
CYCLECAL CHANGES IN BONE REMODELLING
TRAUMA
Osteoclast
activity
Bone
resorption
Osteoblast
activity
Bone
formation
STAGES OF BONE REMODELLING
BONE REMODELLING
ANATOMICAL CHANGES IN BONE MATRIX
Bisphosphonates
In pharmacology,bisphosphonates (also
called:diphosphonates) are a class of drugs that
inhibit osteoclast ...
History
Bisphosphonates were developed in the 19th
century, but were first investigated in the 1960s
for use in disorders ...
OH R-1 OH
O = P C P = O
OH R-2 OH
CHEMICAL STRUCTURE OF BISPHOSPOHONATE
All bisphosphonate drugs share a common P-C-P "bac...
Once a month oral Ibandronate
Alendronate and risedronate are also
nitrogen-containing bisphosphonates
HO
OH
P
O OH
OH
OH
...
Pharmacokinetics
Of the bisphosphonate that is resorbed
(from oral preparation) or infused (for
intravenous drugs), about ...
Mechanism of action
Bisphosphonates, when attached to bone tissue,
are "ingested" by osteoclasts, the bone cell that
break...
Non-nitrogenous
Non-N-containing bisphosphonates:
•Etidronate
•Clodronate
•Tiludronate
The non-nitrogenous bisphosphonates...
Nitrogenous
N-containing bisphosphonates:
•Pamidronate
•Neridronate
•Olpadronate
•Alendronate
•Ibandronate
•Risedronate
•Z...
HMG-CoA reductase pathway
Disruption of the HMG CoA-reductase
pathway at the level of FPPS prevents the
formation of two m...
While inhibition of protein prenylation may affect
many proteins found in an osteoclast, disruption to
the lipid modificat...
Statins are another class of drugs HMG-CoA
reductase pathway. Unlike bisphosphonates,
statins do not bind to bone surfaces...
Uses
Bisphosphonates are used clinically for the treatment of osteoporosis,
osteitis deformans (Paget's disease of the bon...
INDICATIONS
Postmenopausal women with vertebral compression
fractures
Postmenopausal women with total hip bone density
T-s...
Fracture healing
The clinical trials of bisphosphonates have not
reported any increased incidence of fracture non-
union i...
After a fragility fracture (for example, a hip
fracture) in an untreated patient with
osteoporosis, it makes sense to begi...
Side-effects
•Oral bisphosphonates can give stomach upset and inflammation
and erosions of the esophagus, which is the mai...
•Bisphosphonates have been associated with
osteonecrosis of the jaw; with the mandible twice as
frequently affected as the...
Recent studies have reported bisphosphonate use
(specifically zoledronate and alendronate) as a risk
factor for atrial fib...
SIDE EFFECTS
Oral or IV forms Hypocalcaemia
Increased PTH
Skin rash
Atrial fibrillation
Bone pain
Oral forms Upper GI irri...
CONTRA-INDICATIONS
Women who are pregnant or planning pregnancy
Chronic kidney disease stages 4 or 5
Low serum calcium
Ost...
In the large trials the fracture rates with the lower doses were not
significantly different from the rates in higher dose...
PP population
1
Miller PD, et al. J Bone Miner Res 2005;20:1315–22
2
Reginster JY, et al. Ann Rheum Dis 2006;65:654–61
Mon...
Total Hip BMD increases with BisphosphonatesMean%changefrombaselineMean%changefrombaseline
2years2years
TH - 2yrTH - 2yr T...
Treatment : Medications
• Bisphosphonates are first-line drug therapy by
inhibiting bone resorption, bisphosphonates prese...
Treatment : Mode of Use
• Oral bisphosphonates must be taken on an empty
stomach with a full glass of water, and the patie...
Children
Children with severe osteogenesis imperfecta, who have multiple
fractures, show reduction in pain and fracture ra...
Premenopausal women
Bisphosphonates are NOT APPROVED for
prevention of osteoporosis in premenopausal
women. They should no...
Recently postmenopausal women
Alendronate 5mg/day increases bone density compared to placebo, but not as
well as estrogen ...
Estrogen Vs Biphosphonates
Many experts say that bisphosphonates could be used
instead of estrogen in women with osteopeni...
The largest risedronate study included 9331 women: 5445 were 70-
79 years old with T-score lower than -3 and 3886 were old...
Risedronate studies did not show fracture benefit to women older than 80,
even among the women, who had osteoporosis by bo...
Bisphosphonates : Drug InteractionsBisphosphonates : Drug Interactions
• Aminoglycosides: May lower serum calcium
levels w...
• Iron & Magnesium salts:
May decrease the absorption of bisphosphonate
derivatives. Only oral route is of concern.
• Nons...
Advantages:
• They are the most thoroughly investigated agents
we have for the treatment of osteoporosis and the
preventio...
Bisphosphonates : Commonly
Used Pharmacotherapy
Bisphosphonates : Commonly
Used Pharmacotherapy
• Prescribed for 73% of th...
Summery and conclusion
The bisphosphonates are powerful, they cause
dramatic changes in the bone physiology, and they
dese...
HOW LONG THE DRUG CAN BE USED ?
Increased bone density does not necessarily equate with good bone
quality. Bone turnover i...
Osteoporosis  bis-phosphonates dr rabi
Osteoporosis  bis-phosphonates dr rabi
Osteoporosis  bis-phosphonates dr rabi
Osteoporosis  bis-phosphonates dr rabi
Osteoporosis  bis-phosphonates dr rabi
Osteoporosis  bis-phosphonates dr rabi
Osteoporosis  bis-phosphonates dr rabi
Osteoporosis  bis-phosphonates dr rabi
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Osteoporosis bis-phosphonates dr rabi

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OSTEOPOROSIS, BISPHONATES, BONE LOSS, ELDERLY WOMEN, MENOPAUSE, WOMEN , CALCIUM DEFICIENCY, fracture bone

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Osteoporosis bis-phosphonates dr rabi

  1. 1. IN MANAGEMENT OF OSTEOPOROSIS DR. RABI NARAYAN SATAPATHY ASST.PROFESSOR DEPT. OF OBST.& GYNAECOLOGY SCB MEDICAL COLLEGE, CUTTACK MOB-09861281510 EMAIL-drrabisatpathy@gmail.com
  2. 2. OSTEOPOROSIS NOW A GLOBAL PROBLEM
  3. 3. AGE B M D 30 – 35 PROGRESSIVE CHANGE IN BMD WITH AGE N D
  4. 4. CHANGES IN BONE DENSITY WITH AGE
  5. 5. CYCLECAL CHANGES IN BONE REMODELLING TRAUMA Osteoclast activity Bone resorption Osteoblast activity Bone formation
  6. 6. STAGES OF BONE REMODELLING
  7. 7. BONE REMODELLING
  8. 8. ANATOMICAL CHANGES IN BONE MATRIX
  9. 9. Bisphosphonates In pharmacology,bisphosphonates (also called:diphosphonates) are a class of drugs that inhibit osteoclast action and the resorption of bone. Its uses include the prevention and treatment of osteoporosis, osteitis deformans ("Paget's disease of bone"), bone metastasis (with or without hypercalcaemia), multiple myeloma and other conditions that feature bone fragility.
  10. 10. History Bisphosphonates were developed in the 19th century, but were first investigated in the 1960s for use in disorders of bone metabolism. Their non-medical use included water softening in irrigation systems used in orange groves. The initial rationale for their use in humans was their potential in preventing the dissolution of hydroxylapatite, the principal bone mineral, and hence arresting bone loss. Only in the 1990s was their actual mechanism of action demonstrated.
  11. 11. OH R-1 OH O = P C P = O OH R-2 OH CHEMICAL STRUCTURE OF BISPHOSPOHONATE All bisphosphonate drugs share a common P-C-P "backbone" The two PO3 (phosphate) groups covalently linked to carbon determine both the name "bisphosphonate" and the function of the drugs. The long side chain (R2 in the diagram) determines the chemical properties, the mode of action and the strength of bisphosphonate drugs. The short side chain (R1 ), often called the 'hook,' mainly influences chemical properties and pharmacokinetics .
  12. 12. Once a month oral Ibandronate Alendronate and risedronate are also nitrogen-containing bisphosphonates HO OH P O OH OH OH P O N CH3 CH3 Ibandronate OH group at R1 increases affinity for bone mineral N-containing group within R2 increases antiresorptive potency
  13. 13. Pharmacokinetics Of the bisphosphonate that is resorbed (from oral preparation) or infused (for intravenous drugs), about 50% is excreted unchanged by the kidney. The remainder has a very high affinity for bone tissue, and is rapidly absorbed onto the bone surface.
  14. 14. Mechanism of action Bisphosphonates, when attached to bone tissue, are "ingested" by osteoclasts, the bone cell that breaks down bone tissue. There are two classes of bisphosphonate: the N- containing and non-N-containing bisphosphonates. The two types of bisphosphonates work differently in killing osteoclast cells.
  15. 15. Non-nitrogenous Non-N-containing bisphosphonates: •Etidronate •Clodronate •Tiludronate The non-nitrogenous bisphosphonates are metabolised in the cell to compounds that replace the terminal pyrophosphate moiety of ATP, forming a nonfunctional molecule that competes with adenosine triphosphate (ATP) in the cellular energy metabolism. The osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone.
  16. 16. Nitrogenous N-containing bisphosphonates: •Pamidronate •Neridronate •Olpadronate •Alendronate •Ibandronate •Risedronate •Zoledronate 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).
  17. 17. HMG-CoA reductase pathway 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
  18. 18. While inhibition of protein prenylation may affect many proteins found in an osteoclast, disruption to the lipid modification of Ras, Rho, Rac proteins has been speculated to underlie the effects of bisphosphonates. These proteins can affect both osteoclastogenesis, cell survival, and cytoskeletal dynamics. In particular, the cytoskeleton is vital for maintaining the "ruffled border" that is required for contact between that inhibit the a resorbing osteoclast and a bone surface.
  19. 19. Statins are another class of drugs HMG-CoA reductase pathway. Unlike bisphosphonates, statins do not bind to bone surfaces with high affinity, and are thus not specific for bone. Nevertheless, some studies have reported a decreased rate of fracture (an indicator of osteoporosis) and/or an increased bone mineral density in statin users. The overall efficacy of statins in the treatment osteoporosis remains controversial.
  20. 20. Uses Bisphosphonates are used clinically for the treatment of osteoporosis, osteitis deformans (Paget's disease of the bone), bone metastasis (with or without hypercalcaemia), multiple myeloma and other conditions that feature bone fragility. In osteoporosis and Paget's, alendronate and risedronate are the most popular first- line drugs. If these are ineffective or the patient develops digestive tract problems, intravenous pamidronate may be used. Alternatively, strontium ranelate or teriparatide are used for refractory disease, and the SERM raloxifene is occasionally administered in postmenopausal women instead of bisphosphonates. High-potency intravenous bisphosphonates have shown to modify progression of skeletal metastasis in several forms of cancer, especially breast cancer. 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. More recently, bisphosphonates have been used to reduce fracture rates in children with osteogenesis imperfecta.
  21. 21. INDICATIONS Postmenopausal women with vertebral compression fractures Postmenopausal women with total hip bone density T-score below -2.5 Elderly men with non-traumatic fractures Some patients with secondary osteoporosis due to corticosteroids Paget's disease Cancer metastatic to bone Other bone diseases with high bone resorption
  22. 22. Fracture healing The clinical trials of bisphosphonates have not reported any increased incidence of fracture non- union in patients treated with active drug. When bisphosphonates are given to patients after joint replacement surgery, there is less loosening of the prosthesis (Arabmotlagh M, Hilding M, Wilkinson JM) although after 5 years there was no residual positive effect of a dose of pamidronate given at the time of surgery (Shetty N). When given to patients 2 weeks after a fracture of the lower leg, bisphosphonates prevented the bone loss that was seen in the proximal femur of placebo control patients ( van der Poest Clement).
  23. 23. After a fragility fracture (for example, a hip fracture) in an untreated patient with osteoporosis, it makes sense to begin a bisphosphonate. The demonstrated risk of a future fracture is greater than the potential risk of non-union or poor callus remodelling. Of course, these patients need an evaluation for other causes, and concomitant treatment with calcium and vitamin D and physical therapy. It is possible that treatment with anabolic agents will provide even better benefit for the skeleton, but currently bisphosphonates remain the first choice due to their lower cost and greater familiarity
  24. 24. Side-effects •Oral bisphosphonates can give stomach upset and inflammation and erosions of the esophagus, which is the main problem of oral N- containing preparations. This can be prevented by remaining seated upright for 30 to 60 minutes after taking the medication. •Intravenous bisphosphonates can give fever and flu-like symptoms after the first infusion, which is thought to occur because of their potential to activate human γδ T cells. Notably, these symptoms do not recur with subsequent infusions. •There is a slightly increased risk for electrolyte disturbances, but not enough to warrant regular monitoring. In chronic renal failure, the drugs are excreted much more slowly, and dose adjustment is required.
  25. 25. •Bisphosphonates have been associated with osteonecrosis of the jaw; with the mandible twice as frequently affected as the maxilla and most cases occurring following high-dose intravenous administration used for some cancer patients. Some 60% of cases are preceded by a dental surgical procedure and it has been suggested that bisphosphonate treatment should be postponed until after any dental work to eliminate potential sites of infection. A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes
  26. 26. Recent studies have reported bisphosphonate use (specifically zoledronate and alendronate) as a risk factor for atrial fibrillation in women. The inflammatory response to bisphosphonates or fluctuations in calcium blood levels have been suggested as possible mechanisms. One study estimated that 3% of atrial fibrillation cases might have been due to alendronate use.Until now however, the benefits of bisphosphonates generally outweigh this possible risk, although care needs to be taken in certain populations at high risk of serious adverse effects from atrial fibrillation (such as patients with heart failure, coronary artery dise)
  27. 27. SIDE EFFECTS Oral or IV forms Hypocalcaemia Increased PTH Skin rash Atrial fibrillation Bone pain Oral forms Upper GI irritation Esophageal ulceration Intravenous forms Fever Transient leukopenia Eye inflammation Nephrotic syndrome Jaw osteonecrosis Etidronate (Didronel) Osteomalacia Hyperphosphatemia
  28. 28. CONTRA-INDICATIONS Women who are pregnant or planning pregnancy Chronic kidney disease stages 4 or 5 Low serum calcium Osteomalacia Vitamin D deficiency (until it is corrected) Oral bisphosphonates should not be used in: Patients with serious esophageal disease Patients at bed rest who can't stay upright for an hour
  29. 29. In the large trials the fracture rates with the lower doses were not significantly different from the rates in higher doses, despite greater increases in the DEXA measurements with the higher doses. DOSE FOR OSTEOPOROSIS
  30. 30. PP population 1 Miller PD, et al. J Bone Miner Res 2005;20:1315–22 2 Reginster JY, et al. Ann Rheum Dis 2006;65:654–61 Monthly oral Ibandronic acid significantly increases lumbar spine BMD in comparison with oral daily therapy 7 6 5 4 3 2 1 0 Meanchangefrombaseline(%) Year 11 Year 22 3.9 4.9 5.0 6.6 2.5mg daily 150mg monthly p=0.002 p<0.001 n=318 n=320 n=292 n=289
  31. 31. Total Hip BMD increases with BisphosphonatesMean%changefrombaselineMean%changefrombaseline 2years2years TH - 2yrTH - 2yr TH - 2yrTH - 2yr TH - 2yrTH - 2yr IBN monthlyIBN monthly 22 (150mg)(150mg) ALN weeklyALN weekly 11 (70mg)(70mg) RIS weeklyRIS weekly 33 (35mg)(35mg) 3.8 4.1 3.0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 ITT Population 1 Reginster J-Y, et al.Reginster J-Y, et al. Ann Rheum Dis 2006;65:654-61Ann Rheum Dis 2006;65:654-61 2 Rizzoli R, et al. J Bone Miner Res 2002;17:1988-96Rizzoli R, et al. J Bone Miner Res 2002;17:1988-96 3 Harris Curr Med Res Op 2004; Vol 20, No5, 757-764 Non comparative studies
  32. 32. Treatment : Medications • Bisphosphonates are first-line drug therapy by inhibiting bone resorption, bisphosphonates preserve bone mass and can decrease vertebral and hip fractures by 50% • To treat osteoporosis, alendronate can be given at doses of 10 mg once/day or 70 mg once/wk or risendronate at 5 mg once/day or 35 mg once/wk • Ibandronic acid can be given at 2.5mg/day or 150 mg every month. • Parenteral preparations are also available
  33. 33. Treatment : Mode of Use • Oral bisphosphonates must be taken on an empty stomach with a full glass of water, and the patient must remain upright for ≥ 30 min. Weekly therapy is generally preferred for its greater convenience and probably fewer adverse effects • If a patient cannot tolerate oral bisphosphonates, pamidronate or zoledronic acid can be given by IV infusion. However, these have not yet been shown to prevent fractures
  34. 34. Children Children with severe osteogenesis imperfecta, who have multiple fractures, show reduction in pain and fracture rates with bisphosphonates. The radiographs of the long bones show a unique striped pattern when pamidronate is given intermittently, and this is caused by layers of thick bone alternating with osteopenic bone. There may be some weakness in these areas. Currently it is unclear when to stop giving these medications. The drugs are still excreted in the urine 8 years after stopping. Because of uncertainties about long-term effects, these drugs should be used only in serious cases. Children with polyostotic fibrous dysplasia or juvinile Paget's disease may also benefit from bisphosphonates. Again, there are uncertainties about how long to use the medications
  35. 35. Premenopausal women Bisphosphonates are NOT APPROVED for prevention of osteoporosis in premenopausal women. They should not be used in women who got a DEXA out of curiosity and discovered osteopenia. They are beneficial in other situations, such as prolonged high dose steroid use, organ transplantation, fibrous dysplasia, and metastatic carcinoma. Studies in animals show fetal and maternal abnormalities in bones and calcium metabolism, so it is unethical to study this medication in pregnant women or women who might become pregnant while the bisphosphonate is still in the bones.
  36. 36. Recently postmenopausal women Alendronate 5mg/day increases bone density compared to placebo, but not as well as estrogen with norethindrone or estrogen with medroxyprogesterone.
  37. 37. Estrogen Vs Biphosphonates Many experts say that bisphosphonates could be used instead of estrogen in women with osteopenia, to prevent osteoporotic fractures. This is based on wishful thinking instead of evidence. It takes decades to reach "the age of fracture" and we don't know if any drugs except estrogen will work that long. Therefore, presently,bisphosphonates should be used only if the risk of fracture within the next ten years is high enough to justify the potential risks. As more evidence accumulates about long-term benefits, present recommendations may change.
  38. 38. The largest risedronate study included 9331 women: 5445 were 70- 79 years old with T-score lower than -3 and 3886 were older than 80 with either low T-score or a clinical risk factor. BMD was done on 31% of the women older than 80. The graph shows the rates of hip fractures. Those with * were statistically significant Use in elderly patients
  39. 39. Risedronate studies did not show fracture benefit to women older than 80, even among the women, who had osteoporosis by bone densitometry. There is also a possibility that the bisphosphonate does not work as well in women older than 80, because these women may already have low bone formation rate due to inadequate osteoblasts. Use in elderly patients
  40. 40. Bisphosphonates : Drug InteractionsBisphosphonates : Drug Interactions • Aminoglycosides: May lower serum calcium levels with prolonged administration. Concomitant use may have an additive hypocalcemic effect. • Antacids: May decrease the absorption of bisphosphonate derivatives; should be administered at a different time of the day. Antacids containing aluminum, calcium, or magnesium are of specific concern. • Calcium salts: May decrease the absorption of bisphosphonate derivatives. Separate oral dosing in order to minimize risk of interaction.
  41. 41. • Iron & Magnesium salts: May decrease the absorption of bisphosphonate derivatives. Only oral route is of concern. • Nonsteroidal anti-inflammatory drugs (NSAIDs): May enhance the gastrointestinal adverse/toxic effects (increased incidence of GI ulcers) of bisphosphonate derivatives. • Phosphate supplements: Bisphosphonate derivatives may enhance the hypocalcemic effect of phosphate supplements. Bisphosphonates : Drug InteractionsBisphosphonates : Drug Interactions
  42. 42. Advantages: • They are the most thoroughly investigated agents we have for the treatment of osteoporosis and the prevention of fractures in postmenopausal osteoporosis. • They prevent osteoclastic bone resorption, and reduce fracture risk within 12-18 months of treatment initiation. • Given the cost, ease of once-weekly dosing, and minimal side-effects, a biphosphonate is the agent of choice for bone health unless the women has symptoms necessitating estrogen use
  43. 43. Bisphosphonates : Commonly Used Pharmacotherapy Bisphosphonates : Commonly Used Pharmacotherapy • Prescribed for 73% of the 6.3 million physician visits for osteoporosis in the United States in 20031 • Increase BMD at the hip and spine2 • Reduce the risk of fractures2,3 • Have a proven tolerability profile3 • Prescribed for 73% of the 6.3 million physician visits for osteoporosis in the United States in 20031 • Increase BMD at the hip and spine2 • Reduce the risk of fractures2,3 • Have a proven tolerability profile3 1. Stafford RS, et al. Arch Intern Med. 2004;164:1525-1530. 2. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001;285:785-795. 3.Ettinger MP. Arch Intern Med. 2003;163:2237-2246. 1. Stafford RS, et al. Arch Intern Med. 2004;164:1525-1530. 2. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001;285:785-795. 3.Ettinger MP. Arch Intern Med. 2003;163:2237-2246.
  44. 44. Summery and conclusion The bisphosphonates are powerful, they cause dramatic changes in the bone physiology, and they deserve respect. In women or men with a high risk of fractures, these medicines reduce the incidence of fractures and improve the quality of life. The vast advertising in medical and public media has increased the awareness of osteoporosis and possiblity of treatment, which is good, but also has encouraged use of this drug in people who don't really need it. A report by Schousboe found that alendronate is NOT cost-effective in treating women with osteopenia who do not already have an osteoporotic fracture. We still don't know the effects of long-term suppression of bone formation.
  45. 45. HOW LONG THE DRUG CAN BE USED ? Increased bone density does not necessarily equate with good bone quality. Bone turnover is a natural part of maintaining bone health. By decreasing osteoclast activity, micro damage that occur regularly in bone which is normally repaired will hamper after long term use, resulting in increased susceptibility to non spinal fracture with delay healing. The therapeutic efficacy of bisphosphonates in improving bone density and diminishing the risk of fracture is the first five years of therapy,although they are stored in bone for up to 10 years after their consumption is over. Due to shorter metabolic effect,long term use of the drug is doubtful.The drug should be stopped after 5 years.High risk fracture patient requiring longer treatment should be treated with intermittent PTH instead of bisphosphonates.

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