Sophia Ish- Sophia Ish- Shalom Shalom Rambam Medical Rambam Medical Center Center Technion Faculty Technion Faculty of Medicine of Medicine Update on Diagnosis Update on Diagnosis and Treatment of and Treatment of Osteoporosis Osteoporosis
Dec 30, 2015
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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