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Osteoporosis : The Silent Thief

OSTEOPOROSIS has been defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of the bone tissue, with a consequent increase in bone fragility and susceptibility to fracture

Amount of bone resorbed >>> Amount of bone formed by osteoclasts by osteoblasts

¯

BONE LOSS

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Osteoporotic bone remodelling

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Bone Remodelling With Alendronate

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Mode Of Action

Gets preferentially bound under osteoclasts.

Osteoclasts ingest the attached alendronate. Released

alendronate inactivates the osteoclasts. Bone

resorption inhibited.

Alendronate may reduce the number of remodelling

sites

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Mode Of Action (Contd.)

Inhibits cytokine production by osteoblasts

Supports the osteoblast mediated bone formation

Induces the osteoblasts to synthesize a substance which

may directly inhibit the osteoclastic resorption

Alendronate inhibits the osteoclastic bone resorption

without inhibiting the osteoblastic bone formation –

increase in bone mass

Screening Visits

* BMD (< 0.68 g/cm2)* Other eligibility* Vertebral X-ray

VertebralDeformityPresent

VertebralDeformityAbsent

Vertebral Deformity StudyRandomize (N=2027)

3 years

Prim. EndpointNew Vertebral Deformity

Sec. EndpointAll Clinical Fractures

Clinical Fracture StudyRandomize (N=4434)

4.25 years

Prim. EndpointAny Clinical Fracture

Sec. Vertebral Deformity

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Design of the FIT Trial

FIT Trial - Increase in BMD at Femoral Neck

-2

-1

0

1

2

3

4

0 6 12 18 24 30 36

4.1%increase in BMD with Alendronate p<0.001

% o

f p

ati

en

ts

Lancet, 348, 1996Months

alendronate

placebo

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FIT TRIAL - Summary of Fracture Results

Type of fracture % incidence P valuereduction

At least one newvertebral fracture 47 <0.001

Multiple (>2) newvertebral fractures 90 <0.001

Clinical (symptomatic)vertebral fracture 55 <0.001

Hip fracture 51 0.047

Wrist fracture 48 0.013

Lancet, 348, 1996 OSTEOFOS

Alendronate plusHormone Replacement Therapy (HRT)

428 postmenopausal women receiving HRT(average duration of treatment 9.5 years)

Bone mass : > 2 SD below normalAverage age : 62 years

Average duration of menopause : 15 years

214 women continued on HRT for one year

214 women received alendronate 10 mg/day along with HRT for one year

Inpharma 26 Sept’ 1998, No. 1156: 18

3.6%

2.7%

1.7%

1%

0.5%0.8%

0

1

2

3

4

Lumber spine Trochanter Femoral neck

Alendronate plusHormone Replacement Therapy (HRT)

Bo

ne m

ass

HRT alone group

Combination therapy group (alendronate + HRT)

Percentage increases in bone mass from baseline after 1 year’s treatment

Inpharma 26 Sept’ 1998, No. 1156: 18

Addition of Alendronate to Hormone Replacement Therapy (HRT) results in 2 to 5 times greater increase in Bone Mineral Density (BMD) than HRT alone

Steroid-induced Osteoporosis

Majority of bone loss occurs in the beginning (10-20%) 25% may experience a fracture 4 fold increase in all fractures Usually affects vertebrae, ribs, hip Risk higher in patients with higher dose, taking longer,

low BMD etc

Cause

Calcium Urinary Calcium Osteoblastabsorption excretion formation and

function

Alendronate in Steroid-Induced Osteoporosis(Patients receiving 7.5 mg Prednisone)

4

2

0

-212 24 36 48

Lumbar Spine

Me

an

(S

E)

Pe

r ce

nt

Ch

an

ge

in

Bo

ne

Min

era

l D

en

si t

y

+

Week

Placebon=159

5 mg of alendronaten=161

10 mg of alendronaten=157

Age : 17-83 year NEJM 1998; 339: 292-9.

Early Postmenopausal InterventionCohort Study (EPIC)

NEJM 1998; 338(8): 485-492.

1609 postmenopausal women (aged 45 to 59 years)Study Centres : US and Europe

Placebon = 502

Alendronate2.5 mg/day

n = 499

Alendronate5 mg/dayn = 498

Estrogenprogestinn = 110

Hip Bone Mineral Density

0%

20%

40%

60%

80%

100%

Placebo 2.5 mg ofalendronate

5 mg ofalendronate

Estrogen-progestin

>2% gain 2% change >2% loss

Wo

me

n (%

)

NEJM 1998; 338(8): 485-492.

Early Postmenopausal Intervention Cohort Study (EPIC)

Results of US Cohort : Percentage increase in BMD at end of 2 years

Alendronate HRT P

Hip bone 1.3 + 0.3 1.8 + 0.3 P = 0.21

Lumber Spine 2.9 + 0.5 4.0 + 0.3 P = 0.06

Total body 0.8 + 0.3 1.2 + 0.2 P = 0.29

NEJM 1998; 338(8): 485-492.

Annals of Internal Medicine, 1998; 128 : 253-261

Alendronate Osteoporosis Prevention Study Group

447 women < age 40 to 59 years >Duration of menopause : 6 to 36 months before study entry

Duration of trial : 3 years

Placebon = 90

Alendronate1 mg/day

n = 92

Alendronate5 mg/day

n = 88

Alendronate10 mg/day

n = 88

Alendronate20/0 mg/day

n = 89

Alendronate Osteoporosis Prevention Study Group (Contd.)

Annals of Internal Medicine, 1998; 128 : 253-261

0

-3-3

-2

-1

0

1

2

3

4

5

6 12 18Month

Me

an

ch

an

ge

inT

roch

an

ter

Bo

ne

Min

era

l De

nsi

ty,

Pe

rce

nta

ge

Po

ints

24 30 36 0-3

-2

-1

0

1

2

6 12 18Month

Me

an

ch

an

ge

inT

ota

l Bo

dy

Bo

ne

Min

era

l De

nsi

ty,

Pe

rce

nta

ge

Po

ints

24 30 36

Placebo

1 mg/d

5 mg/d

10 mg/d

20/0 mg/d

Mean changes from baseline in Bone Mineral Density

Alendronate in Men with Primary Osteoporosis – Interim Results (12 months) of an Ongoing

Study

0

2

4

6

8

10

Alendronate 10-mg/d+500 mg/d, N=50

Alfacalcidol1mcg/d+500 mg/d,N=62

*

BM

D

Inpharma 1999; No. 1196: Pg 13–14

Lumbar Spine

*p<0.001

*

Femoral Neck

*p<0.04

*

Dosage and Administration

Dosage Prevention of postmenopausal osteoporosis 5 mg/day

Treatment of postmenopausal osteoporosis

10 mg/d

Administration Once-a-day with a full glass of plain water (200 ml) only, on an

empty stomach Patient should not lie down for half an hour after administration Patient should not eat food for half an hour after administration

Contraindications

Abnormalities of the esophagus such as stricture or achalasia

Inability to stand or sit upright for at least 30 minutes

Hypersensitivity to any of the components of this product

HypocalcemiaOSTEOFOS