1-Dr. Samir El Badawy

8/7/2019 1-Dr. Samir El Badawy

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OSTEOPOROSIS

WHERE DO WE STAND NOW?By

Prof. Samir Elbadawy.


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The global osteoporosis therapeutic

market was valued at $9.6 billion in 2009.It is expected to grow to $18.2 billion

by 2017. This significant growth is due

to the strong current treatment optionsas well as to the strong pipeline

candidates. The increased prevalence

of osteoporosis among the femalepopulation is the principle driver of the

osteoporosis market & will continue to be.


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The significant reason for the increase in

the prevalence is due to the decline inthe use of Hormone Replacement

Therapy (HRT) in postemenopausal

women . However recent negative studyresults showed an increased risk of

Stroke , Heart attacks, Breast cancer

and Blood clots have led to a decline

in HRT usage & in addition to increase inthe population will combine to contribute to

the increased burden of osteoporosis.


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Life expectancy in men and women

Age (in years) Expectation of life (in years) in 1999

Male Female

At birth (0) 75.4 80.2

5 71.0 75.7

20 56.2 60.8

30 46.7 51.0

50 27.9 32.0

60 19.4 23.0

70 12.2 15.1

80 7.0 8.7

and life expectancy is increasing

Data from the UK


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Projected number of osteoporotichip fractures worldwide

Projected toreach 3.250million inAsia by 2050

Adapted from Cooper C et al, Osteoporosis Int, 1992;2:285-289

Estimated no of hip fractures: (1000s)

1950

2050

600

3250

1950

2050

668

400

1950

2050

742

3

78

1950

2050

10 0

629

Total number ofhip fractures:

1950 = 1.66 million2050 = 6.26 million


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Clinical syndrome of established senile osteoporosis, H.M.85 y.


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CPO LRR review deck 9

K.P. 29 years

-Asthma bronch.

-Iatrog. Cushing

Multiple vert. Fx

- BMD (T-Score):

L3-L4 - 3,8

Total hip - 3,5- Severe back

pain

- Muscle wasting

Severe Established GIOP after 25 Years GC-Treatment


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Osteoporotic fractures:Comparison with other diseases

1996 new

cases,all ages184 300

750 000vertebral

250 000other sites

250 000forearm

250 000hip

0

500

1000

1500

2000

OsteoporoticFractures

HeartAttack

Stroke BreastCancer

An

nua

lincidencex

1000

1 500 000

annual incidenceall ages

513 000

annual estimatewomen 29+

228 000

annual estimatewomen 30+

American Heart Association,1996American Cancer Society,1996

Riggs BL & Melton LJ 3rd, Bone, 1995;17(5 suppl):505S-511S


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MEASUREMENT OF BONE

MINERAL DENSITY(BMD)


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Dual-energy X-rayabsorptimetry(DXA).

It is currently the standard method formeasuring bone density for the diagnosis

and follow-up treatment of osteoporosis.

However, owing to limitations in itstechnology, DXA is unable to reliably

differentiate between cortical and

trabecular bone and only provides a

measure of areal bone mineral density

(aBMD) using a 2-dimensional approach.


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AP

Spine

Measurement Sites


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Femur

MeasurementSites


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Forearm

Measurement Sites


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OsteomalaciaOsteoarthritis (especially the spine)Vascular calcification (especially the spine)Overlying metal objectsContrast media (spine)

Previous fracture (spine, hip and wrist)Severe scoliosisVertebral deformities due to osteoarthrosis,

Scheuermann`s disease

Problems in the interpretationof BMD by DEXA


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O t ti F t R t d


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0

5

10

15

20

25

30

35

40

45

50

> 1.0 1.0 to 0.5 0.5 to 0.0 0.0 to -0.5 -0.5 to -1.0 -1.0 to -1.5 -1.5 to -2.0 -2.0 to -2.5 -2.5 to -3.0 -3.0 to -3.5 < -3.5

BMD T-scores

0

50

100

150

200

250300

350

400

450

Osteoporotic Fracture Rate andNumber of Women with Fractures

versus BMD

Fractu

resper1000 p

erso

nyears

#W

om

enwithF

rac

tures

Fracture rate# Women with Fractures

Siris, et al, NORA study (web site)


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Quantitative computed tomography

(QCT), which is used less frequentlythan DXA, allows separation of cortical

and trabecular bone and measures bone

mineral density (BMD) 3-dimensionally.QCT is increasingly used in basic and

clinical research to assess BMD as

well as bone geometry. It scans thespine, hip & forearm.


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3D QCT:Evaluates Bone Geometry and Cancellous

and Cortical Bone Density

12

3

4

1

2

3

4

Cortical

Cancellous

HipSpine


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Quantitative Computed Tomography

Advantages

Flexible measurements: pure trabecular bone or mixof cortical and trabecular

Disadvantages

Relatively high radiation dose (100-1000 mR forspine)

Low precision (2-5% error) Expensive No validation of results (WHO, )


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Vertebrae

Hip

Wrist

50 60 70 80

40

30

20

10

Age (Years)

Annu

alinciden

ce

per1

000w

omen

Incidence ofosteoporotic fractures in women

Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72
http://creative.gettyimages.com/source/search/ImageEnlarge.aspx?MasterID=ca60468&s=ImageDetailSearchState%7C3%7C5%7C0%7C6%7C0%7C1%7C0%7C0%7C1%7C38%7C60%7C9%7C1%7C0%7C(%22Une+seule+femme%3ASeulement+des+femmes%22+et+%2260-65+ans%3ASexag%E9naire%22+et+%22T


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Incidence ofosteoporotic fractures in men

Age (Years)

Vertebrae

Hip

Wrist

50 60 70 80

4000

2000

0A

nnu

alincid

en

ce

per1

00,00 0

men

Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72
http://creative.gettyimages.com/source/search/ImageEnlarge.aspx?MasterID=200025263-001&s=ImageDetailSearchState%7C2%7C5%7C0%7C6%7C0%7C1%7C0%7C0%7C1%7C19%7C60%7C9%7C1%7C0%7C(%22Un+seul+homme%3ASeulement+des+hommes%22+et+%2260-65+ans%3ASexag%E9naire%22+et+


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A dangerous vicious circle

lossof autonomy

agony

socialisolation

pain

low bone mass

first fracture

inactivity

new fracture


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WHY DO WE TREATOSTEOPOROSIS?


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PREVENTION OF

THE FIRST

FRACTURE.


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Osteoclast

Inhibition of resorption

Osteoblast

Stimulation of formation

Treatment objectives


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Treatment of osteoporosis:Treatment of osteoporosis:

Challenges of a chronic treatmentChallenges of a chronic treatment

Efficacy on fracturesEfficacy on fractures

Long term safetyLong term safety

Long term complianceLong term compliance


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Management of Osteoporosis

High-Risk Patients

Moderate

(back pain)

Severe

(fractures)Treatment of

Established

Disease

Prevention or

Early diagnosis


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Calcitonin nasal spray:effects on spine and hip -

PROOF Study:analysis at 5 years

100 IU18


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Where are we today?

Bisphosphonates are the therapy of choice fortreating postmenopausal osteoporosis

Potent nitrogen-containing bisphosphonatessignificantly reduce the risk of vertebral andnon-vertebral fractures

Further improvements in therapy convenience,

tolerability and adherence to treatment couldenhance patient management


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Issues with conventional bisphosphonates inpostmenopausal osteoporosis (PMO)

Adherence to therapy is an important considerationwhen optimizing therapeutic outcomes in PMO

Although highly effective and well tolerated, oralbisphosphonates are associated with relativelystringent dosing recommendations

These dosing guidelines may be inconvenient to

some patients and have the potential to reducecompliance


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Poor patient compliance

Data from Downey TW, et al. South Med J. In press.

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12

Months of Continuous Persistence

Daily

Weekly

%

ofPatients

P= NS


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Acute phase response

Upper GI

Rash

Iritis

Renal impairment Jaw osteonecrosis

Bisphosphonate Adverse Events


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Bone Remodeling Process

Resorption

Cavities

Bone

Osteoclasts

Lining Cells

Osteoblasts

Osteoid

Lining Cells

Mineralized

Bone


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High Bone Turnover Leads to Developmentof Stress Risers and Perforations

Stress Risers

Perforations

Bone

Osteoclasts

Options for Prevention and Treatment of Osteoporosis


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GENERAL MEASURES

Recomend.: e.g. Risk of falls, Exercise, Nutrition, Ca/Vit.D-Suppl.Ca/Vit.D-Suppl.

ANALGESIC THERAPY

NSAIDS, Calcitonin, Novaminsulfon, Tramadolol, Opioids

ANTIRESORPTIVE MEDICATIONS

Calcitonin, SERMs, Bisphosphonates, (HRT)

ANABOLIC SUBSTANCES

Teriparatide, Fluoride,Denosumab, GH ?

COMBINATIONS

JDR/KL 05

Options for Prevention and Treatment of Osteoporosis

DUAL ACTION AGENTS

Alfacalcidol,Alfacalcidol, Strontium-ranelate


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HOW LONG TO

TREAT?


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How long to treat ?

HRT: as short as possible ( FDA, NAMS, EMEA)

Raloxifene: no limitation

Teriparatide: 18 months

Strontium Ranelate: at least 5 years

Bisphosphonates: controversial

Denosumab: three years.

T t t f il h t


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Treatment failure: what

to do? What is treament failure? Ensure that drug is taken, is taken appropriately

(BP)

Check BTM Review the diagnosis Decide: - to continue

- switch to IV BP

- add a new drug: no- stop and change: other antiresorptive?

Strontium ranelate? teriparatide?


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Current & future research

I- Skeletal deterioration induced byRANKL infusion:

RANK Ligand produced by osteoblastsis an essential mediator for osteoclast

development.Continuous administrat.

of soluble RANKL in rats created abone loss model.


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II- Improving bone formation and tissue

engineering of large bone defects

through stem cells:

Implantation of autologous osteogenic

cells, named multipotent stromal cells

or mesenchymal stem cells (MSCs).

The human MSCs can differentiate into

adipogenic, chondrogenic, osteogenic

and myogenic lineages.


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This has generated a great deal of

potential clinical use in regenerativemedicine & tissue engineering in the past

decade. Although animal derived MSCs

successfully bridge large bone defects,models for ectopic bone formation as

well as recent clinical trials demonstrate

that bone formation by human MSCs is

inadequate & needs further research.


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III- Use of proton pump inhibitorsand

risk of osteoporosis-relatedfractures:

The use of proton pump inhibitors

has been associated with anincreased risk of hip fractures.

It was found to be both dose

dependent & duration dependent.


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IV- Smoking predicts incident hip

fractures in elderly men:3003 men aged 69 to 80 ys. of age

completed a standard questionnaire

concerning smoking habits & had

BMD of the hip & spine.

Smokers had more incident hipfractures than non-smokers.


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V- A new endocrine pancreas-bone axis:

The skeleton is increasingly recognized

as an important player in the coordinat.

of global energy utilization through itshormonal interaction with other tissues.

Insulin is a central regulator of energy

and glucose balance in the body.


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On one hand, osteoblasts secrete

osteocalcin which may modify both

insulin secretion and sensitivity.

On the other hand, the insulin receptor

is known to be expressed in osteoblasts,

but its exact function in bone and

energetic metabolism has remainedcontroversial.


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VI- Leptin inhibits vitamin D synthesis

through FGF 23 production:

Leptin is a hormone secreted by

adipocytes which controls not only food

intake but also bone mass. Leptin was

reported to decrease renal expression

of the 25-hydroxylase D3,1 alphahydrox-

ylase & thus to decrease the synthesis of

Calcitriol by the renal proximal tubule.


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This study focused on bone-derived

fibroblast growth factor 23 (FGF23) as

a mediator of the influence of leptin on

renal 1 alpha-hydroxylase mRNAexpression in leptin deficient mice.

Exposure to leptin for 24 hs. stimulated

FGF23 expression by primary culturedrat osteoblasts.


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VII- FGF23: a novel predictor of fracture

risk in elderly men:Fibroblast growth factor 23 (FGF23) is a

bone derived circulating factor that

decreases serum conc. of inorganicphosphorus & 1,25-dihydroxy vitamin D3.

Increased FGF23 expression is a direct

or indirect culprit in several skeletaldisorders, however the relationship between

FGF23 & fracture risk remains undetermined.


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VIII- A future new class of bone forming

drugs:Serotinin or 5- hydroxytryptamin (5-HT)

has progressively emerged as an

important regulator of bone remodeling.Serotonin is synthesized in two steps

from the essential aminoacid tryptophan.

It is released by neurons to influencebehavioral, physiological & cognitive functions


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Serotinin is also synthesized outside the

brain mainly by the enterochromaffincells of the gastrointestinal tract.

This gut-derived serotinin(GDS) has been

recently shown to inhibit bone formation byreducing osteoblasts proliferation.

LP533401 is an inhibitor of tryptophan

hydroxylase which when given orally

it reduces circulating but not brain

serotinin levels.


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Every 30 seconds someone in theEuropean Union suffers a hip fracture

as a result of osteoporosis

It is never too late !

A call to action !

Conclusion


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Bone quality is an integral component ofbone strength

Maintaining or restoring bone architectureis required for optimal bone quality

Bone turnover rate affects the degree of

mineralization of bone Optimal collagen/mineral matrix properties

contribute to bone quality

Bone Quality

Turnover Reduction


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Turnover Reduction

Within normal physiologicrange

PreservePreserve

strengthstrength

Decreaseresorption

cavities

Decreasestress risers

Decreaseperforations

MaintainHorizontal struts

MaintainPlate-like structure

Excessive Turnover Reduction


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Excessive Turnover Reduction

Below normal physiologic range

IncreasedIncreased

fragilityfragility

Insufficient fatiguedamage repair

Microcrackaccumulation

Microcrackpropagation

Prolonged secondarymineralization

Excessive mineralization+ homogeneous bone

?

What Is the Optimal Reduction in Bone


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Physiological RangePhysiological Range

Sourced from Weinstein RS, J Bone Miner Res 15 621-625, 2000

What Is the Optimal Reduction in BoneTurnover for an Antiresorptive Drug?

Bo

neS

trength

Bone Turnover

Excessive turnover Increase in stress risers (weak

zones) Increase in perforations Loss of connectivity

Insufficient turnover Accumulation of microdamage Increased brittleness due to

excessive mineralization

Non pharmacological approaches


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Non pharmacological approachesto the prevention of

postmenopausal osteoporosis

Adequate intake of dietary calcium &protein

Regular physical activity

Minimize alcohol intake

Minimize risk of fall

Recommend hip protectors in those proneto falls


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Mineralization Affects Brittleness

**

*

hyper-

mineralized(osteopetrosis)

optimum

hypo-mineralized(osteomalacia)

For

ce

Displacement

Sourced from Turner CH et al. Osteoporos Int13:97-104; 2002


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Bone is Tough and Stiff

collagen

mineral

Osteomalacia

Osteopetrosis

Stiffness

Toug h

ness bone

Regulation of osteoclastogenesis by


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Regulation of osteoclastogenesis byfactors from osteoblast/stromal cells

Hofbauer LC & HeufelderAE, J Mol Med, 2001;79:243-253

Osteoclast precursor

Differentiation

Inhibition

OPG"decoy receptor"

Osteoblast / stromal cell

M - CSF RANK

RANKL

RANKL

Mature osteoclast

Regulation of RANKL and OPG


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Regulation of RANKL and OPGby systemic hormones

Aubin JE & Bonnelye E, Osteoporos Int, 2000;11:905-913

Stimulation

Inhibition

RANKL OPG

17-EstradiolDexametasone1,25-(OH2)D3

PTHPGE2

Hydrocortisone17-Estradiol

1,25-(OH2)D3PTHPGE2

Predicting fracture risk: combining bone


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Predicting fracture risk: combining boneturnover and bone mineral density (BMD)

High rate ofbone resorption(CTX values higher than

the upper limit [mean + 2.0SD]of the premenopausal range)

Low hip BMD(Defined according to WHOcriteria [T-score 2.5])

High rate ofbone resorption +

low hip BMD

0 1 2 3 4 5

Risk of hip fracture (odds ratio)

2.2

2.7

4.8

Adapted from Garnero P, et al. J Bone Miner Res 1996;11:15318

Homogeneous vs


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Homogeneous vs.Heterogeneous Mineralization

Reproduced with permission from Boivin GY et al. Bone 27:687-694; 2000

Heterogeneous Homogeneous

Low mineralization

High Mineralization

H t Mi l


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Heterogeneous MineralDistribution

in Iliac Bone

Reproduced with permission from Boivin GY et al.Bone

27:687-694; 2000

A Pharmacological Agent Should Increase BoneSt th With Mi i l I i B ittl


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Force

Displacement

Treated

Sourced from Turner CH et al. Osteoporos Int13:97-104; 2002

Strength With a Minimal Increase in Brittleness

*

Point of Failure

*

*

Untreated


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Cortical and trabecular


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Cortical and trabecularbone.


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The natural history of bone


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Determinants of Peak Bone Mass

Genetics

Lifestyle

PEAK BONE MASS20-22 years of age

HormonesNutrition


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Bone remodeling

Bone marrow precursorsHematopoietic cellsMesenchymal cells

OsteoblastOsteoclast

Lining cells

Adherence With Bisphosphonates is Poor


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Adherence With Bisphosphonates is Poor

Compliance = medicationpossession ratio(MPR) 80%

Persistence = no gaps in refills >30 days

57% noncompliant

43% compliant

80% non-persistent

20%persistent

Siris ES, et al. Mayo Clin Proc. 2006;81:1013-1022

Based on claims during a 24-monthperiod

Problems with monitoring treatment


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Problems with monitoring treatmentof osteoporosis with DXA

. slow response

. low signal/noise ratio

. the increase in BMD may not be anadequate surrogate marker of efficacy

of all treatments

Garnero P & Delmas PD,Garnero P & Delmas PD, Curr Opin Rheumatol, 2004;16:428-434

Bisphosphonate discovery:


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an intriguing story 1865 First synthesis of a bisphosphonate by

German chemists

1930s Polyphosphates inhibit crystallization ofcalcium salts

1960s Inorganic pyrophosphate preventscalcification of soft tissues and regulatesbone mineralization

1970s and 1980s Bisphosphonates, stable pyrophosphateanalogues, prevent calcification in vitro and

in vivo and inhibit osteoclast mediated boneresorptionTheir profound effects on osteoclastinhibition trigger exploration in a variety ofbone metabolism disorders associatedwith pathologically increased bone resorption

Age and Bone Mass as Predictors


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of Fracture

Hui SL et al. J Clin Invest81:1804-1809;1988

Forearm Bone Mass (g/cm2)

Fractur e

Risk

/1000

Person

Year Age (Years)

0

20

40

60

80

100

120

140

160

>1.0 0.90-0.990.80-0.890.70-0.790.60-0.69


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Age

Impaired gait or balance; lower body muscle weakness

Poor vision; cataracts

Malnutrition; excessive alcohol intake

Certain medical conditions, e.g. arthritis, diabetes, posturalhypotension, cognitive impairment, peripheral neuropathy

Polypharmacy; certain medications, e.g. psychoactive medications,antihypertensives

Footwear with slippery soles, high heels

Factors in the home, e.g. poor lighting, loose rugs, loose cabling,uneven or wet surfaces, bathtubs without handrails or bath mat, clutterat floor level, stepping over pets

Environmental factors, e.g. wet or cracked paving or steps, ice orsnow

Risk factors for falling

Pattern of Gait: YoungPattern of Gait: Young


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CPO LRR review deck 82

Pattern of Gait: YoungPattern of Gait: Young

adultsadults

Pattern of Gait:Pattern of Gait:


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Pattern of Gait:Pattern of Gait:

ElderlyElderly

1-Dr. Samir El Badawy

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