Professional Documents
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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
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
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
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
Mechanics &
Patho Physiology of
Metabolism
& Function Osteo porosis
OSTEOPOROSIS
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 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
= =
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
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
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
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)
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
Slow response
Low signal/noise ratio
The increase in BMD may not be an
adequate surrogate marker of efficacy of all
treatments
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
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
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
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
127.36
Screening
& Diagnosis Monitoring
Risk Assessment
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
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)
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
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
Postmenopausal Senile
Primary
Osteo porosis
INFLAMMAGING
IL6,
CRP,
HSP70,
Stress TNFα, TGFβ
PG, LT, IL10
Coagulation Stochas- LPX
factors ticity Cortisol
Genetics
Environments
Mechanism of Primary Osteoporosis
Estrogen deficiency
↑ IL-1 ↑ IFN-γ
↑ IL-6 MHC II
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
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)
↓ 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
↑ 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
↓ lean mass
DKK 1/
wnt
Osteoid
BMPs, bFGF New bone
↑ 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