OSTEOPOROSIS

WHERE DO WE STAND NOW?

By
Prof. Samir Elbadawy.
 Current Definition of Osteoporosis
Osteoporosis is defined as a skeletal disorder
characterized by compromised bone strength
predisposing a person to an increased risk of fracture.
Bone strength primarily reflects the integration of bone
density and bone quality.

Normal bone
Osteoporosis
NIH Consensus Development Panel on Osteoporosis JAMA 285:785-95; 2001
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 options
as well as to the strong pipeline
candidates. The increased prevalence
of osteoporosis among the female
population is the principle driver of the
osteoporosis market & will continue to be.
The significant reason for the increase in
the prevalence is due to the decline in
the use of Hormone Replacement
Therapy (HRT) in postemenopausal
women . However recent negative study
results 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 in
the population will combine to contribute to
the increased burden of osteoporosis.
 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

 3250
Projected to
Projected number of osteoporotic reach 3.250
million in
hip fractures worldwide Asia by 2050

668
742

400
378

600
195 205

629
0 0
195 205
0 0
Total number of
hip fractures: 195 205
0 0
1950 = 1.66 million 0
10

195 205
0 0
2050 = 6.26 million
Estimated no of hip fractures: (1000s)

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

Clinical syndrome of established senile osteoporosis, H.M.
85 y.
Severe Established GIOP after 25 Years GC-Treatment

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
CPO LRR review deck 9
 Osteoporotic fractures:
Comparison with other diseases

2000 annual incidence

all ages
Annual incidence x 1000

1 500 000
1500
250 000
hip
250 000
forearm
1000 annual estimate
250 000 women 29+
other sites
513 000 annual estimate
women 30+
500
750 000
228 000 1996 new
vertebral 184 300 cases,
all ages
0
Osteoporotic Heart Stroke Breast
Fractures Attack Cancer

American Heart Association,1996

American Cancer Society,1996
Riggs BL & Melton LJ 3rd, Bone, 1995;17(5 suppl):505S-
511S
MEASUREMENT OF BONE
MINERAL DENSITY
(BMD)
Dual-energy X-ray absorptimetry(DXA).
It is currently the standard method for
measuring bone density for the diagnosis
and follow-up treatment of osteoporosis.
However, owing to limitations in its
technology, 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.
 Measurement Sites

AP
Spine
 Measurement Sites

Femur
 Measurement Sites

Forearm
 Problems in the interpretation
of BMD by DEXA

•Osteomalacia
•Osteoarthritis (especially the spine)
•Vascular calcification (especially the spine)
•Overlying metal objects
•Contrast media (spine)
•Previous fracture (spine, hip and wrist)
•Severe scoliosis
•Vertebral deformities due to osteoarthrosis,

Scheuermann`s disease
 Osteoporotic Fracture Rate and
Number of Women with Fractures
versus BMD
50 450
Fractures per 1000 person years

Fracture rate
45 # Women with Fractures
400

# Women with Fractures

40 350
35
300
30
250
25
200
20
150
15
10 100
5 50
0 > 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
0
BMD T-scores
Siris, et al, NORA study (web site)
Quantitative computed tomography
(QCT), which is used less frequently
than 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 the
spine, hip & forearm.
 3D QCT:
Evaluates Bone Geometry and Cancellous
and Cortical Bone Density

Cancellous

2 1
32

3
4
4

Hip
Spine Cortical
 Quantitative Computed Tomography
• Advantages

– Flexible measurements: pure trabecular bone or mix

of cortical and trabecular

• Disadvantages

– Relatively high radiation dose (100-1000 mR for

spine)
– Low precision (2-5% error)
– Expensive
– No validation of results (WHO, …)
 Incidence of
osteoporotic fractures in women
40
Annual incidence
per 1000 women
Vertebrae
30

20
Hip
Wrist
10

50 60 70 80
Age (Years)

Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72

 Incidence of
osteoporotic fractures in men
4000
Annual incidence
per 100,000 men

Vertebrae

Hip
2000

Wrist
0
50 60 70 80
Age (Years)

Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72

A dangerous vicious circle
low bone mass

social
isolation

loss
new fracture pain
of autonomy

agony first fracture

inactivity
WHY DO WE TREAT
OSTEOPOROSIS?
PREVENTION OF
THE FIRST
FRACTURE.
Treatment objectives
Osteoclast Osteoblast

Inhibition of resorption Stimulation of formation

 Treatment of osteoporosis:
Challenges of a chronic treatment

• Efficacy on fractures

• Long term safety

• Long term compliance

Management of Osteoporosis

Severe Treatment of
(fractures) Established
Moderate Disease
(back pain)

Prevention or
High-Risk Patients
Early diagnosis
 Calcitonin nasal spray:
effects on spine and hip -
PROOF Study:analysis at 5 years

Reduction in % of new vertebral Number of hip

fractures vs placebo fractures per group
0 25
10
20
20
30 100 IU 400 IU
40 18<% 23%
(NS) 200 IU 15
50 (NS)
33% 7
60
(P=0.03) 10 8 (NS)
70 4
80 2 (NS)
90 5 (NS)
100
0
Placebo 100 IU 200 IU 400 IU

N=511 NS = non significant

Chesnut CH 3rd et al, Am J Med, 2000;109:267-276

 Where are we today?

• Bisphosphonates are the therapy of choice for

treating postmenopausal osteoporosis
• Potent nitrogen-containing bisphosphonates
significantly reduce the risk of vertebral and
non-vertebral fractures
• Further improvements in therapy convenience,
tolerability and adherence to treatment could
enhance patient management
Issues with conventional bisphosphonates in
postmenopausal osteoporosis (PMO)

• Adherence to therapy is an important consideration

when optimizing therapeutic outcomes in PMO

• Although highly effective and well tolerated, oral

bisphosphonates are associated with relatively
stringent dosing recommendations

• These dosing guidelines may be inconvenient to

some patients and have the potential to reduce
compliance
 Poor patient compliance
100
90
80
70
% of Patients

Daily
60
Weekly
50
40
30
20
10
0
1 2 3 4 5 6 7 8 9 10 11 12
Months of Continuous Persistence
P = NS
Data from Downey TW, et al. South Med J. In press.
Bisphosphonate Adverse Events

• Acute phase response

• Upper GI
• Rash
• Iritis
• Renal impairment
• Jaw osteonecrosis
 Bone Remodeling Process
Osteoclasts
Resorption
Cavities
Lining Cells

Bone

Lining Cells Osteoblasts

Mineralized Osteoid
Bone
 High Bone Turnover Leads to Development
of Stress Risers and Perforations
Osteoclasts

Bone

Perforations

Stress Risers
Options for Prevention and Treatment of Osteoporosis

COMBINATIONS

DUAL ACTION AGENTS

Alfacalcidol, Strontium-ranelate

ANABOLIC SUBSTANCES
Teriparatide, Fluoride,Denosumab, GH ?

ANTIRESORPTIVE MEDICATIONS
Calcitonin, SERMs, Bisphosphonates, (HRT)

ANALGESIC THERAPY
NSAIDS, Calcitonin, Novaminsulfon, Tramadolol, Opioids

GENERAL MEASURES
Recomend.: e.g. Risk of falls, Exercise, Nutrition, Ca/Vit.D-Suppl.
JDR/KL 05
HOW LONG TO
TREAT?
 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.
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?
 Current & future research
I- Skeletal deterioration induced by
RANKL infusion:
RANK Ligand produced by osteoblasts
is an essential mediator for osteoclast
development.Continuous administrat.
of soluble RANKL in rats created a
bone loss model.
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.
This has generated a great deal of
potential clinical use in regenerative
medicine & 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.
III- Use of proton pump inhibitors and
risk of osteoporosis-related
fractures:
The use of proton pump inhibitors
has been associated with an
increased risk of hip fractures.
It was found to be both dose
dependent & duration dependent.
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 hip
fractures than non-smokers.
V- A new endocrine pancreas-bone axis:
The skeleton is increasingly recognized
as an important player in the coordinat.
of global energy utilization through its
hormonal interaction with other tissues.
Insulin is a central regulator of energy
and glucose balance in the body.
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 remained
controversial.
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.
This study focused on bone-derived
fibroblast growth factor 23 (FGF23) as
a mediator of the influence of leptin on
renal 1 alpha-hydroxylase mRNA
expression in leptin deficient mice.
Exposure to leptin for 24 hs. stimulated
FGF23 expression by primary cultured
rat osteoblasts.
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 inorganic
phosphorus & 1,25-dihydroxy vitamin D3.
Increased FGF23 expression is a direct
or indirect culprit in several skeletal
disorders, however the relationship between
FGF23 & fracture risk remains undetermined.
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 influence
behavioral, physiological & cognitive functions
Serotinin is also synthesized outside the
brain mainly by the enterochromaffin
cells of the gastrointestinal tract.
This gut-derived serotinin(GDS) has been
recently shown to inhibit bone formation by
reducing osteoblasts proliferation.
LP533401 is an inhibitor of tryptophan
hydroxylase which when given orally
it reduces circulating but not brain
serotinin levels.
 Conclusion
Every 30 seconds someone in the
European Union suffers a hip fracture
as a result of osteoporosis

A call to action !

It is never too late !

 Bone Quality
• Bone quality is an integral component of
bone strength
• Maintaining or restoring bone architecture
is required for optimal bone quality
• Bone turnover rate affects the degree of
mineralization of bone
• Optimal collagen/mineral matrix properties
contribute to bone quality
 Turnover Reduction
Within normal physiologic
range

Decrease
Decrease perforations
resorption
cavities
Maintain
Plate-like structure
Decrease
stress risers
Maintain
Horizontal struts

Preserve
strength
 Excessive Turnover Reduction
Below normal physiologic range

Prolonged secondary
Insufficient fatigue
mineralization
damage repair

Excessive mineralization
+ homogeneous bone
Microcrack
accumulation Microcrack

? propagation

Increased
fragility
 What Is the Optimal Reduction in Bone
Turnover for an Antiresorptive Drug?
Insufficient turnover Excessive turnover
• Accumulation of microdamage • Increase in stress risers (weak
• Increased brittleness due to zones)
excessive mineralization • Increase in perforations
• Loss of connectivity
Bone Strength

Physiological Range

Bone Turnover
Sourced from Weinstein RS, J Bone Miner Res 15 621-625, 2000
 Non pharmacological approaches
to 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 prone
to falls
 Mineralization Affects Brittleness
hyper-
* mineralized
(osteopetrosis)

* optimum
Force

hypo-
* mineralized
(osteomalacia)

Displacement
Sourced from Turner CH et al. Osteoporos Int 13:97-104; 2002
 Bone is Tough and Stiff

collagen bone
Toughness

Osteomalacia

mineral
Osteopetrosis

Stiffness
Regulation of osteoclastogenesis by
factors from osteoblast/stromal cells
Osteoclast precursor Mature osteoclast

Differentiatio
n

M - CSF RANK Inhibition

OPG
RANKL "decoy receptor"

RANKL

Hofbauer LC & Heufelder

Osteoblast / stromal cell AE, J Mol Med, 2001;79:243-
253
Regulation of RANKL and OPG
by systemic hormones

RANKL OPG
•Dexametasone •17â-Estradiol
•1á,25-(OH2)D3
•PTH
•PGE2
Stimulation

•17â-Estradiol •Hydrocortisone
•1á,25-(OH2)D3
•PTH
•PGE2
Inhibition

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

 Predicting fracture risk: combining bone
turnover and bone mineral density (BMD)
High rate of
bone resorption
(CTX values higher than 2.2
the upper limit [mean + 2.0SD]
of the premenopausal range)

Low hip BMD

(Defined according to WHO 2.7
criteria [T-score ≤ –2.5])

High rate of
bone resorption + 4.8
low hip BMD

0 1 2 3 4 5
Risk of hip fracture (odds ratio)

Adapted from Garnero P, et al. J Bone Miner Res 1996;11:1531–8

 Homogeneous vs.
Heterogeneous Mineralization

Heterogeneous Homogeneous

Low mineralization

High Mineralization

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

 Heterogeneous Mineral
Distribution
in Iliac Bone

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

 A Pharmacological Agent Should Increase Bone
Strength With a Minimal Increase in Brittleness

* Treated

*
Force

Untreated

Displacement
Sourced from Turner CH et al. Osteoporos Int 13:97-104; 2002 *Point of Failure
Cortical and trabecular
bone.
The natural history of bone
Determinants of Peak Bone Mass

Genetics

PEAK BONE MASS

Nutrition Hormones
20-22 years of age

Lifestyle
 Bone remodeling
Bone marrow precursors
Mesenchymal cells Hematopoietic cells

Osteoclast
Osteoblast Lining cells
 Adherence With Bisphosphonates is Poor

Based on claims during a 24-month

period

57% noncompliant 80% non-persistent

20%
43% compliant persistent

Compliance = medication Persistence = no gaps in refills >30 days

possession ratio (MPR) ≥ 80%

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

Problems with monitoring treatment
of osteoporosis with DXA

. slow response

. low signal/noise ratio

. the increase in BMD may not be an

adequate surrogate marker of efficacy
of all treatments

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

 Bisphosphonate discovery:
an intriguing story
• 1865 First synthesis of a bisphosphonate by
German chemists
• 1930s Polyphosphates inhibit crystallization of
calcium salts
• 1960s Inorganic pyrophosphate prevents
calcification of soft tissues and regulates
bone mineralization
• 1970s and 1980s Bisphosphonates, stable pyrophosphate
analogues, prevent calcification in vitro and
in vivo and inhibit osteoclast mediated bone
resorption
Their profound effects on osteoclast
inhibition trigger exploration in a variety of
bone metabolism disorders associated
with pathologically increased bone resorption
 Age and Bone Mass as Predictors
of Fracture
160 Age (Years)
Fracture Risk / 1000 Person Year

140 80+

120
75-79
100

80 70-74
60
65-69
40 60-64
55-59
20 50-54
45-49
<45
0
>1.0 0.90-0.99
0.80-0.89
0.70-0.79
0.60-0.69 <0.60
Forearm Bone Mass (g/cm2)
Hui SL et al. J Clin Invest 81:1804-1809;
1988
 Risk factors for falling
• Age
• Impaired gait or balance; lower body muscle weakness
• Poor vision; cataracts
• Malnutrition; excessive alcohol intake
• Certain medical conditions, e.g. arthritis, diabetes, postural
hypotension, 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, clutter
at floor level, stepping over pets
• Environmental factors, e.g. wet or cracked paving or steps, ice or
snow
Pattern of Gait: Young
adults

CPO LRR review deck 82

Pattern of Gait:
Elderly

CPO LRR review deck 83