1-dr. samir el badawy
TRANSCRIPT
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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