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Mechanics &

Patho Physiology of
Osteo porosis
Damayanti T
Department of Physical Medicine & Rehabilitation
School of Medicine Airlangga University/
Dr. Soetomo General Hospital
Structure & Force

Mechanics &
Physiology of
Metabolism
& Function Osteo
• Mineral Reservoir
• GF & Cytokine Depository
• Fat Repository
• Acid – base Equilibrium
• Detoxification
• Endocrine Function
350  206 bones
Functions :
Structural & Metabolic

• Structural support
• Framework for motion
• Protection
• Mineral and fat storage
• Housing of blood cells
and stem cells
Bone Tissue Types
• Compact bone :
Dense tissue that form outer bone
layer (marrow space < bone
tissue) and mostly be in long
bones.

• Spongy/cancellous bone :
Marrow space > bone tissue, as a
bone marrow producer. Mostly be
in short, flat and irregular bones.
Factors Affect the Bone
Mechanical Loading
Local Tissue Genotype
Interactions

Nutrition

Drugs

Metabolic factors Disease

Hormones
Physiology of
Metabolism
& Function Osteo
“Bone is Dynamic Tissue”
Frostian Model : Modeling vs Remodeling
Define skeletal shape, Maintain proper serum level ions,
Repair structurally compromised regions of bone

• bone forming in GROWING


BONE until skeletal
maturity is reached in size,
shape & position 
involve Activation- • in ADULT SKELETON  involve Activation-
Resorption or Activation- Resorption-Formation, as coupling
Formation, separated) process
• depend on : • done by BMU
• Power muscles
growth
• Increased body mass
• Lengthened diaphysis

Manolagas SC, 2000. Birth and Death of Bone Cells: Basic Regulatory Mechanisms and Implications for the Pathogenesis and Treatment of
Osteoporosis. Endocrine Reviews 21(2): 115–137
Factors Affect Bone Cells
PTH, T4 Estrogen
Vit A & D Progesteron
Cortisol Testosteron

PDGF
VEGF
Calcitonin,
PG, IL4,
IL18, IFNγ

Osteoid
BMPs, bFGF New bone

IGF-1 Old bone


IL-6, IL-1, IL-11, M-CSF TGF-β
Structure & Force
Mechanics

of
Osteo
The diminishing returns
(loading time-desentization,
rest time-resentization)
The dynamic stimulus Bone cells
accommodate to
routine loading
(local bone memory,
cell’s mechanosensitivy,
cell accomodation)

MECHANO-
TRANSDUCTION
RULES THAT GOVERN
BONE ADAPTATION
Bone Physiologic Adaptation

H. Frost. The Utah Paradigm of Skeletal Physiology


Structure & Force

Mechanics &
Patho Physiology of
Metabolism
& Function Osteo porosis
OSTEOPOROSIS

A WHO working group &


CDC (1991) : US NIH (2000) :
A systemic silent A skeletal disorder
progressive skeletal disease

Compromise
↓ Bone Mass
Bone Strength

↑ Bone
fragility
Micro-
architectural
deterioration
The Bone Gain vs Loss During Life
SHIFTING THE OSTEOPOROSIS PARADIGM
“Bone Strength”
NIH Consensus Statement 2000

Bone Strength Bone Quality and Bone Quantity

Bone size
Architecture Bone mass
Micro damage Bone mineral density
Collagen quality
Mineralization
Static - BMD Bone turnover rate
Dynamic - BCBM
15
Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001
THE IMPORTANCE OF ARCHITECTURAL INTEGRITY

10% decrease in BMD due to 10% decrease in BMD due to


loss in trabecular thickness loss in trabecular number

= =
20% reduction in bone strength 70% reduction in bone strength
Silva MJ, Gibson LJ. Bone 1997:21;191–9 ; Parfitt AM. Am J Med 1991; 91 (Suppl5B):42S-46S.
FRACTURE RISK :
Bone quality is not the only factor…
Neuromuscular function Fall characteristics Bone size (mass)
Environmental risks Energy absorption Bone shape
Age External protection Architecture
Matrix properties

Fall Fall Bone


incidence impact strength

Fracture risk
Screening & Detecting

Osteo porosisDamayanti T
Department of Physical Medicine & Rehabilitation
School of Medicine Airlangga University/
Dr. Soetomo General Hospital
How should patients be evaluated to
determine if they have osteoporosis?
AACE AACE Osteoporosis Task Force. Endocr Pract 2003;9:545–64
http://www.nof.org/professionals/clinical.htm

• Comprehensive medical
examination
• X-rays in patients with suspected
vertebral fractures
NOF • BMD measurements
• Assessment of risk factors for
fractures
• Biochemical Bone Marker
Management of Disability due to Osteoporosis
Disability Aim Target Action
Prevention
Level I Promotive – Healthy Education about osteoporosis
impairment people Detection/screening of osteoporosis risk factors (OMORT,
prevention Major Risk Factor, Calcium Intake Estimation, OSTA, US)
Management of changeable osteoporosis risk factors
(endocrine, meal, posture and physical activity)
Level II Disability Osteopenic Education about osteoporosis and osteoporotic fracture
prevention and Identification of osteoporotic fracture risk (Fall Risk
osteoporotic Assessment, DEXA, FRAX, Biochemical Bone Marker)
patients Management of changeable osteoporotic fracture risk
(endocrine, meal, posture, physical activity and risk of
fall)
Increase quality of life (active and safe life style)
Level III Handicap Osteoporotic Education about osteoporosis, osteoporotic fracture and
prevention fracture complications
patients Identification of complication risk factors post
osteoporotic fracture
Management of complication risk factors as much as
possible
Prevention of new fracture
Maintain and increase quality of life (promote
independency)
Screening Tools for Osteoporosis Risk
Major Risk Factors
• Age > 60 years
• Low body weight • Posture alignment
• Genetic • Kyphotic
• Paternal and maternal • Dowager hump
family history of • Habit
osteoporosis fractures • Alcoholism > 3 unit/day
• Gender, ethnicity • Smoking
• Endocrine • Activity
• Hypogonadism • Sedentary
• Prolonged gluocorticoid • Immobilization
use • Recurrent Falls
• Hyperparathyroidism • Disease
• Meal • Rheumatoid arthritis
• Calcium intake, • Diabetes mellitus
• Vitamin D intake • Malabsorption (coeliac)
• Vitamin K intake
IOF - International Osteoporosis Foundation, 2012
Screening Tools for Osteoporosis Risk
Estimation of Calcium Intake

Langkah 1 : Perkiraan asupan kalsium dari makanan kaya kalsium(*)

Produk Porsi/hari Perkiraan kalsium/ Kalsium (mg)


porsi (mg)
Susu (250 cc) x 300 =
Yogurt (200 cc) x 300 =
Keju (20 cc) x 200 =
Makanan/jus fortifikasi x 80-1000 (**) =
Langkah 2 : Total di atas + 250 mg dari sumber non susu Kalsium
= kalsium makanan total ____________ mg
(*) 75-80% kalsium yang dikonsumsi di Amerika berasal dari produk susu
(**) Kandungan kalsium pada berbagai makanan fortifikasi
Screening Tools of Osteoporosis Risk

Evidence :
Qaseem et al., 2008 : OSTA risk index on red area had a Sn of 70-90% and Sp 70%
Lu et al., 2006 : Sn, Sp, and accuracy of OSTA risk index with T score cutoff of LS BMD :
• -2.5 were 59.1%, 56.9% and 57.8%,
• -2.0 were 57.5%, 63.1%, 59.6%
Screening Tools of Osteoporosis Risk
Bone Ultrasound (QUS)
• Cheaper than DEXA
• Reproducibility not as good as DEXA
• Ultrasound of the calcaneus and
DEXA of the hip both predict relative
risk of hip fracture
• Fracture prediction is independent of
DEXA
– ultrasound with DEXA does not
enhance prediction
• In-vitro studies show that ultrasound
mainly measures bone mass
– DEXA predicts bone strength better
Pongchaiyakul et al., 2007 : the nomogram can assist primary care physicians in the identification of high-risk people
Identification Tools for Osteoporosis Fracture Risk
Risk Factors for Falls
Intrinsic Risk Factors Extrinsic Risk Factors Environment Risk
Factors
General deterioration associated with Personal hazards Hazards indoors or at
ageing (Inappropriate home
(Poor postural control, defective footwear or (Bad lighting, steep
proprioception, reduced walking speed, clothing) stairs, lack of grab
weakness of legs, slow reaction time, rails, slippery floors,
various comorbidities) Multiple drug loose rugs, pets,
therapy grandchildren’s toys,
Problems with balance, gait, or mobility (Sedatives, cords for telephone
(Joint disease, cerebrovascular disease, Hypotensive and electrical
peripheral neuropathy, Parkinson’s drugs) appliances)
disease, alcohol, various drugs)
Hazards outdoors
Visual impairment (Uneven pavements,
(Impaired visual acuity, cataracts,glaucoma, streets, paths, lack of
retinal degeneration) safety equipment,
slippery conditions,
Impaired cognition or depression traffic and public
(Alzheimer’s and cerebrovascular diseases) transportation)
“Blackouts”
(Hypoglycaemia, postural hypotension,
cardiac arrhythmia, TIA, acute onset
CVA, epilepsy, vertebrobasilar
insufficiency, carotid sinus syncope,
neurocardiogenic (vasovagal) syncope Woolf et al. BMJ 2003; 327:89-95
Identification Tools for Fall Risk
(sensitivity, 73%; specificity, 55%)

(sensitivity, 87%;
specificity, 29%)

Delbaere K, Close JCT, Menz HB, Cumming RG, Cameron ID, Sambrook PN, March LM and Lord SR, 2008. Development and
validation of fall risk screening tools for use in residential aged care facilities Med J Aust 189 (4): 193-196
Identification Tools for Fall Risk
Prevent Falls = SAVES BONE
Shoe
Alcohol
Visit the environment
Evaluation of visus
Sedative
Balance
Orthostatic hypotension
Night lamps
Exercise
Risk Factors for Fracture
Major Risk Moderate Risk Strong Risk (RR>2)
(1<RR<2)
• Prior fragility • Rheumatoid arthritis • Menopause < 45
fracture • Bechterew disease • Glucocorticoids
• Increased age • Anticonvulsants • Immobilization
• Low bone mineral • Calcium intake < 500 • BMI < 19
density mg/d • Anorexia
• Low body weight • Diabetes mellitus Nervosa
• Family history of • Estrogen deficiency • Propensity to fall
osteoporotic • Primary • Malabsorption
fracture hyperparathyroidism • Chronic renal
• Glucocorticoid use • Hyperthyroidism failure
• Smoking • Smoking • Transplantation
• Alcohol excess • Hypogonadism
Kanis et al. Osteoporos Int. 2005; 16:581-9
Identification Tools for
Osteoporosis Fracture Risk

A. Wall-Occiput Test : if wall-occiput distance > 0 cm shows possibility of occult thoracic vertebral fractures.
B. Rib-Pelvis Distance : if costa-crista iliaca distance <2 fingerbreath shows possibility of vertebral fracture
(Green AD, Colon-Emeric CS, Bastian L, Drake MT, Lyles KW. JAMA.2004;292:2890-900. Copyright (c) 2004 American Medical Association).
X-ray Osteoporotic Vertebral Fracture

Genant HK, et al. J Bone Miner Res 1996;11:984–96 http://courses.washington.edu/bonephys/opclin.html


Measurement of Vertebral deformity
SD=standard deviation
Reproduced from J Bone Miner Res 1991;6:207-15 with permission of the American Society for
Bone and Mineral Research
Identification Tools for Osteoporosis Fracture Risk
Fracture risk calculation – FRAX

www.sheffield.ac.uk/FRAX
Left Femur FRAX*

Risk Factors:
√ None

Alcohol (3 or more units per day)
Family Hist (Parent hip fracture)
Glucocorticoids (Chronic)
History of Fracture (Adult)
Secondary Osteoporosis
Rheumatoid Arthritis
Tobacco User (Current Smoker)

10-year Probability of Fraaacture:


Major Osteoporotic 12.0%
Hip 4.4%
Population Hongkong
Based on Femur (Left) Neck BMD
DIAGNOSIS OF OSTEOPOROSIS
Bone Densitometry – Dual X-ray Absorptiometry
Diagnosis of Osteoporosis
Bone Densitometry – Dual X-ray Absorptiometry

• The diagnosis of osteoporosis is based on simple,


painless X-ray methods called densitometry (dual-
energy X-ray absorptiometry - DXA)  measure
‘bone mineral density’ or BMD (g/cm2) 
standardization is expressed as T Score
• BMD is positively associated with bone strength
& resistance to fracture, but not reflects
interconnectivity of the trabecular
Indications for BMD Testing

• Women age >65 and men age >70, regardless of


clinical risk factors
• Younger postmenopausal women and men age 50-69
about whom concerned based on their clinical risk
factor profile
• Women in the menopausal transition if there is a
specific risk factor associated with increased fracture
risk such as low body weight, prior low-trauma fracture
or high risk medication
• Adults who have a fracture after age 50
• Radiographic evidence of bone loss
Indications for BMD Testing
• Adults with a condition (e.g., rheumatoid arthritis) or taking
a medication (e.g., glucocorticoids in a daily dose ≥ 5 mg
prednisone or equivalent for ≥ 3 months) associated with
low bone mass or bone loss
• Asymptomatic hyperparathyroidism where osteoporosis
would suggest parathyroidectomy
• Anyone being considered for pharmacologic therapy for
osteoporosis
• Anyone being treated for osteoporosis, to monitor
treatment effect
• Anyone not receiving therapy in whom evidence of bone
loss would lead to treatment
• Postmenopausal women discontinuing estrogen should be
considered for bone density testing
.
Information from AACE Clinical practice guidelines for the prevention and treatment of post-menopausal osteoporosis. Endocrin Pract 1996;2(2):157–71
BMD, Age and Osteoporosis

Osteopenia

Osteoporosis

85
Normal
75
65
WHO gold standard for osteoporosis diagnosis 55
(WHO Study Group. WHO Technical Report Series
843, Geneva Switzerland: WHO;1994:1–129) : 45
1. T-score of BMD 35
2. Osteoporotic fracture 25
1,300 1,100 900 700 500

Standardised total hip BMD


2 • 1 SD is at the 16th percentile
(white women, mg/cm )
• 84% of young women have
normal bone density
Interpretation of Serial BMD Measurements

• Continued BMD loss exceeding the LSC may reflect


– Poor adherence to therapy
– Failure to respond to therapy
– Previously unrecognized secondary causes of
osteoporosis
• Most anti-osteoporosis therapies do not cause large
BMD increases  Stable BMD is consistent with
successful treatment

Chen P, et al. J Bone Miner Res 2009; 24(3):495-502.


LSC : 0.028 (d=0.016 ↑ ns) LSC : 0.029 (d=0.029 ↑ s)
Recommendations for Monitoring Therapy
 ISCD :
 Follow-up BMD testing (DXA spine and hip) when :
 the expected change in BMD > LSC (1yr after initiation) or
 change of therapy
 Longer intervals once therapeutic effect is established
 More frequent in conditions associated with rapid bone
loss (i.e glucocorticoid therapy)
 AACE : annual DXA of the LS and proximal femur
until stability is achieved & every 2yrs thereafter
 NAMS : DXA of the total hip every 2yrs
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


Recommendations for Monitoring Therapy

Bone turnover markers role in not available DXA


If DXA cannot be performed at 1y  measure fasting
serum CTX (s-CTx) before and 3-6 months after starting
antiresorptive therapy.
If the marker has fallen significantly (by 50%), the
patient can be reassured that the next BMD
measurement will likely be stable or improved.
Repeat DXA can be done in 2yrs.
Identification Tools for Osteoporosis Fracture Risk
Value of Bone Turnover Assessment
Measuring markers of bone resorption and bone
formation may help to provide
– more rapid assessment of response to therapy
– independent evaluation of fracture risk
– better patient selection
– enhanced compliance
Factors that Affect Bone Remodeling
Intra individual
variation 20-30% Age
Time of day - diurnal Sex
Diet Race
Activity Fracture
Season Disease
Pregnancy/menstrual cycle Medications

Osteoid

New bone

Old bone
In untreated patients : In treated patient :
Predicting bone loss & Bone Turnover Markers Monitoring the
response to treatment
fracture risk

Bone turnover can be measured using biochemical bone markers in serum and
urine, can be split into bone formation & resorption markers  show the change
number of bone site which underwent remodeling process (Eastell et al, 1997)
Bone Formation Bone Resorption

Bone specific alkaline Free crosslinks


phosphatase (BALP) (PYR, DPD)

C-terminal
- collagen I
degradation products
Osteocalcin
N-terminal collagen I
degradation products

Type I C-terminal
Collagen propetides peptide (ICTP)
(PNIP, PCIP)

Osteoblasts Osteoclasts
In treated patient :
Monitoring the
Bone Turnover Markers response to treatment

Treatment Bone Significant


Turnover changes (after
Markers 3 months)
Anabolic agent P1NP ↑>10µg
Antiresorptive agent CTx ↓70% ↓ 40% vertebral fracture risk
P1NP ↓50% ↓ 44% vertebral fracture risk
Energetic catabolic ↓ 30%–40%
(raloxifene)
Guidelines for Bone Markers
International Osteoporosis Foundation (IOF) Recommendations
Monitoring of Antiresorptive Agents
How often ?
• Measure bone markers before starting treatment and
• 3 months or 6 months for resorption markers after treatment has been
initiated
• 6 months for formation markers after treatment has been initiated

When ?
• Serum markers: Measure before 9:00 am after an overnight fast
• Urine: either first or second morning void, with creatinine correction,
after an overnight fast

Which ?
• Bone Resorption: S-/U-CTX and U-NTX, U-DPD
• Bone Formation: BAP, NMid-osteocalcin, and P1NP

Source: Delmas PD, et al. Osteoporos Int. 2000;6:S2-S17.


sCTx, sNMid and sCTx/sNMid ratio
Mean of
sCTx sNMid sCTx/sNMid
pg/dL ng/dL ratio pg/ng
Tinduh & Roeshadi, 2003
67 women 45-64 y 450.30 29.46 15.3
+272.48 +12.71 +5.6
23 women > 65 y 411.91 27.33 15.4
+203.57 +13.16 +5.8
Normal post menopausal value from 556 + 226 41.3 13.5
Elecsys ® data
Mehta’s study
134 American Post menopausal 570 32.1 17.7
women
Chailurkit’s study, 2000 420 17.21 24.35
214 Thai Post menopausal women +30 +1.35 +.15
Identification Tools for Osteoporosis Fracture Risk
Biochemical Bone Marker
(Tinduh & Retnowati, 2012)
P1NP CTx P1NP/CTx
ng/mL ng/mL
Premenopausal 40.4 + 15.5 0.3 + 0.1 172.6 + 57.8
Females
Postmenopausal 60.5 + 11.6 0.5 + 0.1 119 + 24.6
Females
Males < 65 yo 56.2 + 20.1 0.5 + 0.2 129.1 + 41.7

Males > 65 yo 50.4 + 17.5 0.4 + 0.1 132.8 + 44.3


Biochemical Bone Marker Monitoring
Case : Woman, 84 yo, Low energy fracture,
Dx (X-ray) : Severe Osteoporosis + Fr. Ramus Inf Pubis D
Tx : Bone antiresorptive drug
CTx (pg) NMid (ng) CTx/NMid (pg/ng)
36.2 Cut Off ratio for CTx/NMid :
1230
33.99 Females >16.61 pg/ng (Fast bone loser)

27.25
24.4
22.99 22.39
* 19.91 20.26
18.81 18.48
17.53 17.87 17.69 17.76
16.62 17.07 16.29
15.78 15.53
13.98 13.22 13.51
12.23 444
403 11.8 396 11.8
385 10.37
334
269 *
297 287
239
* 177 171 156 *

27-12-07 20-10-09 21-01-10 24-06-10 25-11-10 26-05-11 24-11-11 18-06-12 18-12-12 01-04-13 22-07-13 24-01-14 08-09-14
Biochemical Bone Marker Monitoring
Case : Woman, 55 yo, 5y postmenopause
Tx : Play Speed Walking Exercise, 30 minutes, 3x/w for 3 weeks

P1NP (ng) CTx (ng) P1NP/CTx


Cut Off ratio for
0.405 Osteogenic P1NP/CTx :
* 70.25
243.92 Females > 129.2
Males > 132.3
51.58 0.288

127.36

Pre Exercise Post 3w Exercise


ineral Density versus Bone Markers in Osteoporosis Dia

Bone Mineral Density (BMD)


 Mainly used for  Gold standard  Meaningful results
screening for diagnosis 3 only available after
1-2 years 4,5

Screening
& Diagnosis Monitoring
Risk Assessment

 Good evidence  Not recommended 1  Ideal application


for risk assessment 1 for bone markers;
Bone Markers meaningful results
 Best used together
available after 3
with BMD 2
months1

1. Delmas PD, et al. Osteoporos Int. 2000;6:S2-S17.,


2. Kanis JA. Lancet. 2002;359:1929-1936.
3. US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD:
US Department of Health and Human Services, Office of the Surgeon General; 2004.
4. Christgau S, et al (2000) Bone Vol.26, No.5
5. Roux C, et al. (2005) Joint Bone Spine 72: 26–31
Mineral Density versus Bone Markers in Therapy Monito
Check
Treatment Check
Efficacy Compliance ?

Therapy Monitoring with Bone Markers Months


0 3 6 9 12 16 20 24
Baseline

• Bone Markers are reliable indicators of therapeutic success as early as


three months after start of therapy 3
Check Treatment Efficacy &
Therapy Monitoring with a Radiological Method Compliance Months
0 3 6 9 12 16 20 24
Baseline
• First follow-up only possible after 1-2 years 1,2
for Bone Mineral Density (BMD).
• The precision error of BMD measurements
varies from 1%-5% 1.

1. Christgau S, et al (2000) Bone Vol.26, No.5, 2. Roux C, et al. (2005) Joint Bone Spine 72: 26–31
3. Delmas PD, et al. Osteoporos Int. 2000;6:S2-S17.
BONE MARKERS
Surrogate Marker Of Choice
For Early Treatment Monitoring 1

Least Significant Change (LSC):


Only changes greater than the precision error reflect real biological changes!

• Better signal to noise-ratio for BTM during first year of treatment 2


• Easier to detect a 50% change with BTM than a 3% change in BMD after 3-6
months of therapy 3
References:
1 Vasikaran SD et al. Clinical Reviews in Clinical Laboratory Sciences 2008.
2 Reginster JY et al. Bone 2008
3 Srivastata AK et al. Curr Med Res Opin 2005.
Identification Tools for Osteoporosis Fracture Risk
Predicting fracture risk:
Combining Biochemical Bone Marker and BMD
High rate of
2.2
bone resorption*

Low hip BMD† 2.7

High rate of
bone resorption + 4.8
low hip BMD

0 1 2 3 4 5
Risk of hip fracture (odds ratio)
*C-telopeptide of the alpha chain of type 1 collagen (CTX) >mean + 2 SD of premenopausal range
†Defined according to WHO criteria (T-score –2.5)

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


New Patient
Major risk factors assessment

Detection/Screening of
• Age
1 Low OSTA

Osteoporosis Risk
Body weight
• Genetic
No • Endocrine
OMORT Medium-
• Meal and intake
High
Yes • Posture alignment
• Habit
Osteoporosis • Activity
< 0.3 QUS • Recurrent Falls
Risk Nomogram
• Disease

> 0.3

Osteoporotic Fracture Risk


not available
DEXA FRAX

Identification of
+1 to -1
available

-1 to -2.5
< -2.5

Low High

Blood Examination

Detection of Bone
Primary
Osteoporosis Status of BTO rate :

Loss Rate
not available
underlying P1NP/CTx,
disease CTx/NMid
Secondary
available
Osteoporosis
Treat underlying disease Slow Loser Fast Loser
2 3
Classification of
Osteo porosis
Classification of Osteoporosis

Children Female Male

Low turn over High turn over Primary


Primary Secondary Secondary
state state Senile

Postmenopausal Senile
Primary
Osteo porosis
INFLAMMAGING

IL6,
CRP,
HSP70,
Stress TNFα, TGFβ
PG, LT, IL10
Coagulation Stochas- LPX
factors ticity Cortisol

PRO Microbiota ANTI


Epigenetics

Genetics

Environments
Mechanism of Primary Osteoporosis

Type I Type II (Senile)


(Postmeno- Osteoporosis
pausal) ↓ replicative of
Osteoporosis osteoprogenitor cells
↓ sEstrogen ↓ synthetic activity
↑ IL-1, IL-6, OB
TNF ↓ biologic activity of
↑ RANK & matrix-bound GF
RANKL ↓ physical activity
↑ OC
activity
Postmenopausal Osteoporosis

Estrogen deficiency

↓Intestinal ↑ Renal Calcium


Calcium excretion
↑ IL-7 T-cell activation absorption

↑ IL-1 ↑ IFN-γ

↑ IL-6 MHC II

↑ PGE2 T-cell activation

↑ TNF-α ↑ RANKL ↑ PTH

↓ OPG ↑ Osteoclast regeneration

Bone loss
Stem Cells changes in
Postmenopausal Women
Tinduh & Retnowati, 2012 :
Percentage of MSC in PBMC Premenopause Postmenopause
(n=38) (n=22)
Bone Marrow derived-MSC 0.6% 0.4%
(CD34-CD105+CD49d-)
Adipose derived-MSC 3.5% 0.2%
(CD34-CD105+CD49d+)
Integrin 40.2% 0.7%
(CD34-CD105-CD49d+)
Osteoblast Progenitor 0.5% 0.2%
(CD117-CD116-CD184+)
Systemic Inflammation
Age related dysregulation Age related functional decline
of differentiation

Impaired level of MSC


system signals MSC
(hormone, cytokine, GF)
• ↑ apoptosis
• ↓ regeneration
Impaired • AbN differentiation
epigenetic • ↓ mobilization
regulation • ↓ homing &
engrafting
Niche Impaired
aging ECM HSC
HSC
Pino et al, 2012;
Tinduh & Retnowati, 2012;
Georgen et al, 2013

CTx

Muscle P1NP

Bone Matrix
Bone marrow Peripheral circulation
Male Osteoporosis
MULTIFACTORIAL :
• Age related bone loss : Combination of nutritional & hormonal
deficiencies (Khosla et al 2008)
– ↓ intestinal calcium absorption
– high prevalence of vitamin D insufficiency and deficiency
contribute to elevated serum PTH levels & bone loss (Lips 2001).
– Estrogen & testosterone (Falahati-Nini et al 2000; Leder et al 2003; Amin et al
2006)
– ↓ IGF-1 & ↑ insulin-like growth factor binding protein 2 (IGFBP-2)
levels impair bone formation directly or via an ↑ serum SHBG levels
(Amin et al 2004, 2007).
• Secondary osteoporosis : 85% of cases are caused by glucocorticoid,
hypogonadism & excessive alcohol intake (Ebeling 1998, 2008)  in the
majority of younger men with osteoporosis (Orwoll and Klein 2001) and
may be superimposed on primary osteoporosis (Khosla et al 2008).
• Most responsible inflammatory factor : IFNƴ
Bone Loss Pattern: Male vs Female
• Trabecular bone (predominantly found in the
vertebrae), begins to decline before midlife in both
sexes, but to a lesser extent in men, with 42% of
trabecular bone being lost before age 50 (Riggs et al 2008)

• Cortical bone mass remains relatively stable until


midlife, then decreases linearly in both men and
women, with the decline being greater in females (Riggs
et al 2008), occurs later in life from around the age of 65
years in men

• as the total surface available for trabecular remodeling


decreases, causing bone remodeling to move from the
trabecular to cortical compartment (Seeman 2002)
Metabolism Humoral
↓ Physical activity Nutrition ↓ Testosteron
↑ Oxydative stress Malnutrition ↓ Estrogen
↑ Cytokine ↓ GH
(inflammation) ↓ IGF-1
Weight Loss
Adapted from Kvell et al, 2011. Molecular and
Clinical Basics of Gerontology. University of Pécs
Xue Q. Clin Geriatr Med 27 (2011) 1–15
Sarcopenia
Frailty VO2max/ energy
exhaustion
↓ Physical Activity

↓ Strength Osteoporosis ↓ BMR

↓ Walking speed
↓ Total Energy Impaired
Expenditure Thermoregulation
Impaired balance Stiff + pain
on LE

Osteoporotic
↑ Tend to /
Fear of Falls
↑ Falls
Fracture Impaired ADLs
Secondary
Osteo porosis
HIGH RISK FOR SECONDARY
OSTEOPOROSIS
• Severe chronic liver or kidney diseases
• Steroid medication (>7.5mg for more than 6 months)
 85% of cases
• Malabsorption (eg. Crohn´s disease)
• Rheumatoid arthritis
• Systemic inflammatory disorders
• Hyperthyroidism
• Primary hyperparathyroidism
• Antiepileptic medication
• Hypogonadism
• Excessive alcohol intake
LABORATORY EXAMINATION FOR
SECONDARY OSTEOPOROSIS
First line screening Extended assessment
• Complete blood count (CBC), • immunoelectrophoresis,
• chemistry profile, • insulin-like growth factor-1 (IGF-
• functional metabolic profile of urine 1),
organic acids, • homocysteine,
• urine pH,
• dehydroepiandrosterone (DHEA),
• urine calcium/creatinine ratio,
• serum 25-hydroxyvitamin D, • follicle-stimulating hormone (FSH),
• serum calcium and phosphorus, • parathyroid hormone (PTH),
• tissue transglutaminase anti-body, • vitamin B12,
• CTx, • cortisol,
• thyroid-stimulating hormone (TSH), • food-allergy testing,
• estrogen, • stool analysis,
• testosterone, • salivary secretory IgA,
• sex hormone-binding globulin (SHBG)
• and others

McCormick RK, 2007. Osteoporosis: Integrating Biomarkers and Other Diagnostic Correlates into the Management of Bone Fragility.
Alternative Medicine Review Volume 12, Number 2
PEDIATRIC OSTEOPOROSIS
• 1st Pediatric Consensus Development Conference on the
use and interpretation of bone density studies in
children (sponsored by the ISCD, Montreal, June 2007)
– Pediatric Osteoporosis = BMD Z score < -2 + fracture
– No terminology of osteopenia when related to pediatric
BMD or BMC
• Pathophysiology : bone formation - bone resorption
rate imbalance
– low-turnover : chronic liver disease, burn injuries,
conditions affect bone marrow (eg, malignancies) or their
treatments ↓ bone formation
– high-turnover: Paget disease or hyperparathyroidism,
preterm infants, trauma and infection or threat of infection
 ↑ bone resorption
DISUSE OSTEOPOROSIS
• Immobilization effect on musculoskeletal system induces
– Bone loss secondary to ↑ in resorption and ↓ in formation in the
WB bones  uncoupling bone remodeling  universal mechanism
of disuse-induced bone loss
– Muscle atrophy in parallel to bone loss, mainly at the level of
antigravity muscles
• Muscle activity without load seems insufficient to prevent
bone loss
• Factors that may influence the bone loss in immobilization :
– hypothalamic control of energy expense,
– influence of PTH levels on Ca2+ & P metabolism,
– variations in serotonin levels
DISUSE OSTEOPOROSIS

Disuse of Bone
(low stress)
↓ bone formation
Growing Bone on periosteal
surfaces

↑ bone resorption
on endocortical &
trabecular surfaces
Mature Bone
↑ bone turnover
on endocortical &
trabecular surfaces
Rapid
Bone Loss
Robling et al, 2006. Biomechanical and Molecular Regulation of Bone
Remodeling. Annu. Rev. Biomed. Eng. 8:455–98
OSTEOPOROSIS in
NEUROMUSCULAR DISEASE
Cognitive
Dysfunction
Emotion
Locomotor
Motivation Dysfunction
Weakness
Sedentary
Incoordination

↓ muscle ↓ WB Spasticity
contraction

Low bone stress

↑ Bone loss

Osteoporosis
OSTEOPOROSIS in SCI
• Osteoporosis has been seen on x-ray as early as 6w after injury
 typically levels off around 2y after injury
• 80% chronic SCI patient have either osteopenia /osteoporosis
• Complete injuries >> bone loss incomplete injuries
• Spasticity / NMES help maintain bone mass after SCI due to
muscle pulling on the bone, similar to the effect of WB – but it
still a contradiction
• Causes Osteoporosis in SCI
– Disuse
– Disordered vasoregulation
– Poor nutritional status
– Hormonal alterations (testosterone, PTH, glucocorticoids, calcitonin)
– Metabolic disturbances in metabolites and acidity of the blood
– Autonomic nervous system disregulation
OSTEOPOROSIS in
CARDIOVASCULAR DISEASE

↓ physical
activity
during
childhood

Chronic
inflammation

Low Peak Bone


Mass

↓ physical Low bone


activity stress
↑ bone loss Osteoporosis
OSTEOPOROSIS in
PULMONARY DISEASE
OSTEOPOROSIS in
RHEUMATO-IMMUNOLOGY DISEASE
OSTEOPOROSIS in
RHEUMATO-IMMUNOLOGY DISEASE
Inflammatory Disease

Hypogonadism Inflammation Nutrition Immobilization

↓ lean mass

IFN-γ TNF-α/ ↓ leptin/


TNF-α
IL-1β/ IGF-1/
IL-17 estradiol

DKK 1/
wnt
Osteoid
BMPs, bFGF New bone

IGF-1 Old bone


IL-6, IL-1, IL-11, M-CSF TGF-β
OSTEOPOROSIS in
RHEUMATO-IMMUNOLOGY DISEASE
Excess Glucocorticoid

↓ Calcium ↓ Sex steroids ↓ Growth ↓ Muscle mass & strength


absorption/ factors/wnts ↓ Mechanosensing
reabsorption

↑ PTH

↓Proliferation,
↑ Apoptosis,
↓ Bone formation
↑ Survival,
↓Apoptosis,
Osteoid
↑Bone resorption
BMPs, bFGF New bone

↑ Apoptosis,
IGF-1
↑ Skeletal fragility
IL-6, IL-1, IL-11, M-CSF TGF-β Old bone
OSTEOPOROSIS and DEPRESSION
CONCLUSION
• Shifting paradigm : osteoporosis as disease 
disorder ; bone mass  bone strength
• Osteoporosis actually is clinical manifestation of
aging bone, which affected by multiple risk factors
• Bone boosters, bone and systemic
microenvironment are important factors for bone
health
• Knowing the pathophysiology and pathomechanic
of osteoporosis is important for its management
THANK YOU

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