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Update on Diagnosis and
Treatment of Osteoporosis
Sophia Ish-Shalom
Rambam Medical
Center
Technion Faculty of
Medicine
Diagnosis 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
Kuopio
Sheffield
Gothenburg I
Rotterdam
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
To be Used at the WHO Model
• Age
• Ever corticosteroid use
• BMD
• Family history of fracture
• BMI
• Current smoker
• Prior fracture
• >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
High 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
High 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
– Patients 113
– Women 87(78%)
– Men 26 (22%)
28 (29.5%)
Non-osteoporotic BMD at all measurements sites, no
previous fractures
Osteoporotic BMD at least at one measurement
site or previous fracture
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
Aart C Kooijman and Frans
W Cornelissen
JBMR November 2005,
Volume 20, Number 11
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.
Absolute vs. Relative Risk
• Absolute Risk
Incidence or prevalence rate
For example 100 smokers are followed for 1 year.
If 6 of them fracture the absolute fracture risk is
6/100 = 6%
• Relative Risk
Ratio of absolute risks for 2 groups
For example, if absolute risk of fracture is 6% in
smokers and 2% in non smokers the relative risk
of fracturing is 6/2 = 3
It Often Takes Time to Reach the Diagnosis
S Ish-Shalom
Effects of Treatments on
Lumbar-spine Bone Mineral Density
• Fluoride
• GH
Bone Formation drug • IGF1
• Srontium
• PTH 1-84
• PTHrP
Antiresorptive drug • PTH 1-34
1.2
1.1
1.0
Placebo
0.9
-1
0
1
2
Year
3
4
S Ish-Shalom
Strontium ranelate
Similar to calcium: absorbed in the gut; incorporated in
bone; elimination through the kidneys.
-
Ranelic acid
OOC
CH2
CN
100 g/gr bone
CH2
Sr++
-
OOC
S
COO -
N
Sr++
CH2
CO O-
Protelos - Les laboratoires Servier
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 Studies
bone formation, at least in certain pre-osteoblastic cell systems
the bone resorption activity of osteoclasts.
 osteoclast apoptosis at higher concentrations
Marie et al. Calc Tiss Int 2001; 121-129
Effects of Strontium
Ranelate on BMD
Serum Biochemical Markers
of Bone Metabolism.
Spinal Osteoporosis Therapeutic Intervention (SOTI
)Meunier et al NEJM 2004
Mean % Changes in Spine BMD From Baseline to 3 Years in
Patients Receiving Active Treatment in Four Clinical Trials
atomic number of strontium (Z = 38) vs. calcium (Z = 20).
Blake and Fogelman JBMR Nov 2005
Human Parathyroid Hormone
1-34 and 1-84
hPTH (1-34)
1
H2 N -Ser
10
Val Ser
Glu
Ile
Gln Leu
Met
His Asn
Leu
20
Glu
Val Arg
Gly
Glu Met Ser
Asn Leu His
Lys
Trp
Leu
Arg Lys
Lys Leu Gln Asp Val
His
Asn Phe
30
40
50
60
70
hPTH/PTHrP
Receptor
80
-
COOH
hPTH 1-34
Adapted from Proc Natl Acad Sci USA (1974);71:384
Adapted from Jin et al. J Biol Chem (2000);35:27238
(crystal structure)
2004
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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