Sophia Ish-ShalomSophia Ish-ShalomRambam Medical Rambam Medical

CenterCenterTechnion Faculty of Technion Faculty of

MedicineMedicine

Update on Diagnosis and Update on Diagnosis and Treatment of OsteoporosisTreatment of Osteoporosis

Diagnosis of OsteoporosisDiagnosis of Osteoporosis

What do we want to know about risk?

How likely is that this individual with

osteoporosis will sustain a fracture over

a finite period of time?

Cohort Studies

EVOS/EPOS Hiroshima CaMos

Rochester Sheffield Rotterdam

Kuopio Gothenburg I Gothenburg II

Epidos Dubbo OFELY

N=59,232 Person Years = 249,898 % Female = 74

Any fracture = 5444

Osteoporotic Fractures = 3495

Hip Fractures = 957

Independent Risk Factors Independent Risk Factors To be Used at the WHO ModelTo be Used at the WHO Model

• Age

• BMD

• BMI

• Prior fracture

• Ever corticosteroid use

• Family history of fracture

• Current smoker

• >2U alcohol/day

There is a growing consensus that intervention thresholds

should be based on absolute risk (probability) of fracture

rather than diagnostic thresholds

Identification of Osteopenic Women at Identification of Osteopenic Women at High Risk of Fracture: The OFELY StudyHigh Risk of Fracture: The OFELY Study

Prospective cohort study: 671

median follow-up 9.1 years: BMD, Fracture

confirmation

postmenopausal women age >62

158 incident fractures in 116 women: 8% in

normal, 48% in osteopenic, and 44% in

osteoporotic women. Sornay-Rendu et al JBMR Oct 2005

Survival probability without fracture in postmenopausal women according to the WHO criteria of BMD

Identification of Osteopenic Women at Identification of Osteopenic Women at High Risk of Fracture: The OFELY StudyHigh Risk of Fracture: The OFELY Study

In postmenopausal women with osteopenia:

• age

• low BMD( -2) – (-2.5) HR 2.5 (1.3-4.6).

• increased bone turnover markers BALP HR 2.2 for 1/4

• prior fracture HR (age adjusted) 2.2 (1.2- 4.3)

risk of fracture in the subsequent 10 years for one factor present (26% vs 2%).

Sornay-Rendu et al JBMR Oct 2005

BMD and Previous Fractures in Hip Fracture Patients

2828 ( (29.5%29.5%))

Non-osteoporotic BMD at all measurements sites, no Non-osteoporotic BMD at all measurements sites, no previous fracturesprevious fractures

Osteoporotic BMD at least at one measurement Osteoporotic BMD at least at one measurement site or previous fracturesite or previous fracture

– Patients 113Patients 113

– Women Women 87(78%)87(78%)

– Men 26 (22%)Men 26 (22%)

E.Segal et al

Better Lighting to Reduce Falls and Fracture? A Comment on de Boer et al. (2004): Different Aspects of Visual Impairment as Risk Factors for Falls and Fractures in Older Men and Women

Investments in the daily living conditions and improving the

visibility of the elderly visual environment will presumably reduce

their risk of falling and fractures, in turn resulting in savings on

medical and care expenses.

Aart C Kooijman and Frans W Cornelissen JBMR November 2005, Volume 20, Number 11

Absolute vs. Relative RiskAbsolute vs. Relative Risk

• Absolute RiskAbsolute Risk

Incidence or prevalence rateIncidence or prevalence rate

For example 100 smokers are followed for 1 year. For example 100 smokers are followed for 1 year.

If 6 of them fracture the absolute fracture risk is If 6 of them fracture the absolute fracture risk is

6/100 = 6%6/100 = 6%

• Relative RiskRelative Risk

Ratio of absolute risks for 2 groupsRatio of absolute risks for 2 groups

For example, if absolute risk of fracture is For example, if absolute risk of fracture is 6%6% in in

smokers and smokers and 2%2% in non smokers the relative risk in non smokers the relative risk

of fracturing is of fracturing is 6/2 = 36/2 = 3

S Ish-Shalom

It Often Takes Time to Reach the Diagnosis

S Ish-Shalom

Effects of Treatments onLumbar-spine Bone Mineral Density

Placebo

Antiresorptive drug

Bone Formation drug

-1 0 1 2 3 4Year

0.9

1.0

1.1

1.2

Lu

mb

ar-S

pin

e B

one

Min

eral

Den

sity

(g/

cm2 ) •Fluoride

•GH•IGF1•Srontium•PTH 1-84•PTHrP•PTH 1-34

Strontium ranelateStrontium ranelate

Sr++

S N

CN

Sr++

CH2

H2

C CO -O

CO -O

OC- O

OC- O

H2

C

Protelos - Les laboratoires Servier

Ranelic acid

Similar to calcium: absorbed in the gut; incorporated in bone; elimination through the kidneys.

100 g/gr bone

Strontium - Bone Retention

• In the short term the strontium atoms are adsorbed

on to the surface of hydroxyapatite crystals

• In the longer term some strontium will exchange

with calcium in the bone mineral and may remain

bound in the skeleton for years

• The exchange is limited with maximum replacement

by strontium, when given in high doses, of one in

every ten calcium atoms.

Strontium – Bone Retention• ICRP model predicts that at 3 months, 1 year, and 3 years after a

single oral dose of strontium, the skeleton retains 20%, 15%, and

11%, respectively, of the strontium absorbed by the gut

• Three-year treatment with strontium ranelate at 2 g/day total

strontium intake of 750 g. 25% absorption by the gut

• Using the ICRP model to calculate the average long-term

retention after a 3-year treatment, there is 30 g of strontium in

the skeleton.

• Expressed as a molar fraction of the total calcium content in bone

=1% (i.e., after 3 years of treatment with strontium ranelate, there

is 1 strontium atom for every 100 calcium atoms in bone tissue).

In Vitro StudiesIn Vitro Studies

Marie et al. Calc Tiss Int 2001; 121-129

bone formation, at least in certain pre-osteoblastic cell systemsthe bone resorption activity of osteoclasts. osteoclast apoptosis at higher concentrations

Effects of Strontium Ranelate on BMD

Serum Biochemical Markers Serum Biochemical Markers of Bone Metabolismof Bone Metabolism.

Spinal Osteoporosis Therapeutic Intervention (SOTI )Meunier et al NEJM 2004

Mean % Changes in Spine BMD From Baseline to 3 Years in Mean % Changes in Spine BMD From Baseline to 3 Years in Patients Receiving Active Treatment in Four Clinical TrialsPatients Receiving Active Treatment in Four Clinical Trials

Blake and Fogelman JBMR Nov 2005

atomic number of strontium (Z = 38) vs. calcium (Z = 20).

1 10

20

30

Ser Val Ser Glu Ile Gln Leu Met His AsnLeu

GlyLysHisLeuAsnSerMetGluArgValGlu

Trp

LeuArg Lys Lys Leu Gln Asp Val His Asn Phe

50

40

6070

80

- COOH

H2 N -

hPTH 1-34(crystal structure)Adapted from Proc Natl Acad Sci USA (1974);71:384

Adapted from Jin et al. J Biol Chem (2000);35:27238

Human Parathyroid Hormone1-34 and 1-84

2004

hPTH/PTHrPReceptor

hPTH (1-34)

Cumulative Proportion Of Women Enrolled In The Follow-up Study Who Had One Or More Nonvertebral Fragility Fractures

After Baseline By Kaplan-Meier Analysis

Prince et al JBMR Sep 2005

Doctors are men who

prescribe medicines of

which they know little, to

cure diseases of which

they know less, in human

beings of whom they know

nothing.

Francois-Marie Arouet - Voltaire 1694 - 1778

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