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

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. OSTEOPOROSIS NOW A GLOBAL PROBLEM

5. AGE
B
M
D
30 – 35
PROGRESSIVE CHANGE IN BMD WITH AGE
N
D

6. CHANGES IN BONE DENSITY WITH AGE

7. CYCLECAL CHANGES IN BONE REMODELLING
TRAUMA
Osteoclast
activity
Bone
resorption
Osteoblast
activity
Bone
formation

8. STAGES OF BONE REMODELLING

9. BONE REMODELLING

10. ANATOMICAL CHANGES IN BONE MATRIX

11. 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.

12. 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.

13. 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
.

14. 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

15. 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.

16. 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.

17. 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.

18. 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).

19. 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

20. 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.

21. 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.

22. 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.

23. 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

24. 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).

25. 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

26. 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.

27. •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

28. 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)

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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.

38. Recently postmenopausal women
Alendronate 5mg/day increases bone density compared to placebo, but not as
well as estrogen with norethindrone or estrogen with medroxyprogesterone.

41. 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.

42. 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

43. 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

44. 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.

45. • 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

46. 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

49. 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.

51. 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.

52. 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.