IN

MANAGEMENT OF OSTEOPOROSIS DR. RABI NARAYAN SATAPATHYASST.PROFESSORDEPT. OF OBST.& GYNAECOLOGYSCB MEDICAL COLLEGE, CUTTACKMOB-09861281510EMAIL-drrabisatpathy@gmail.com

OSTEOPOROSIS NOW A GLOBAL PROBLEM

AGE

BMD

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 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.

HistoryBisphosphonates 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.

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.

Once a month oral Ibandronate

Alendronate and risedronate are alsonitrogen-containing bisphosphonates

HOOH

PO OH

OH

OHP

ON

CH3

CH3

Ibandronate

OH group at R1 increases affinity for bone mineral

N-containing group within R2 increases antiresorptive potency

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.

Mechanism of actionBisphosphonates, 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.

Non-nitrogenousNon-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.

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).

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

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.

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.

UsesBisphosphonates 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.

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

Fracture healingThe 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).

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

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.

•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

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)

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

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

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

PP population1Miller PD, et al. J Bone Miner Res 2005;20:1315–222Reginster 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

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6

5

4

3

2

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m b

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(%)

Year 11 Year 22

3.9

4.9 5.0

6.62.5mg daily150mg monthly

p=0.002

p<0.001

n=318 n=320 n=292 n=289

Total Hip BMD increases with BisphosphonatesM

ea

n %

ch

ange

from

bas

elin

eM

ea

n %

ch

ange

from

bas

elin

e2

yea

rs2

yea

rs

TH - 2yrTH - 2yr TH - 2yrTH - 2yr TH - 2yrTH - 2yr

IBN monthlyIBN monthly 22

(150mg)(150mg)ALN weeklyALN weekly 11

(70mg)(70mg)RIS weekly RIS weekly 33

(35mg)(35mg)

3.84.1

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

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ITT Population1 Reginster J-Y, et al. Reginster J-Y, et al. Ann Rheum Dis 2006;65:654-61Ann Rheum Dis 2006;65:654-612 Rizzoli R, et al. J Bone Miner Res 2002;17:1988-96Rizzoli R, et al. J Bone Miner Res 2002;17:1988-963 Harris Curr Med Res Op 2004; Vol 20, No5, 757-764

Non comparative studies

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

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

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

Premenopausal womenBisphosphonates 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.

Recently postmenopausal women

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

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.

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

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

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.

• 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

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

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.

Summery and conclusionThe 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.

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.