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‫بسم هللا الرحمن الرحيم‬
Zahra Rezaieyazdi. MD.
Professor of Rheumatology
Ghaem Hospital
MUMS
19 AUG 2014
‫جامي است که عقل افرين ميزندش‬
‫صد بوسه ز مهر بر جبين ميزندش‬
‫اين کوزه گر دهرچنين جام لطيف‬
‫ميسازد و باز بر زمين ميزندش‬
‫خيام‬
OSTEOPOROSIS
DEFINITION
 Disturbed
balance between the
activity of bone producing and bone
resorbing cells
 Low
bone density
 Deterioration
of bone micro-
architecture
Reduce bone strength and
BONE
BONE LINING
CELLS
Osteoprogenitor cells
Osteoblasts
Osteoclast
Cell process
©Copyright 2007, Thomas G. Hollinger, Gainesville, Fl
BONE STRUCTURAL UNIT
BONE REMODELING:
Osteoclast precursors
DIFFERENTIATION
1. systemic
factors
2. 1,25dihydroxyvita
min D,
3. parathyroid
hormone
4. tumor
necrosis factor
(TNF)
5. thyroxin
RANKL
PATHWAY
M-CSF
CALCIUM HOMEOSTASIS - PTH ACTION
-ve feedback
PTH
1:25-DHCC
Decreased
Ca Clearance
Increased
Ca Absorption
Plasma/ICF
Ca++
Increased Ca
Turnover
with
Net Resorption
DETERMINANTS OF PEAK BONE MASS
Genetics
Nutrition
PEAK BONE MASS
20-22 years of age
Lifestyle
Hormones
ESTROGEN
Increase osteoblast proliferation
 Attenuate the osteoblast response to PTH
 Osteoblastic collagen gene expression
 IGFII production
 inhibiting RANKL production and increasing
production of the protein OPG
 Bone mineral density in men as well as women is
dependent on sufficient estrogen levels

BONE MASS AS A FUNCTION OF AGE
PEAK BONE MASS
NORMAL
FAILURE TO REACH PEAK
ACCELERATED LOSS
BONE
MASS
THEORETICAL
FRACTURE
THRESHOLD
AGE
Effects of aging on Bone Loss:
-ESTROGEN DEFICIENCY
-REDUCE OPG LEVELS
-DECREASE ABSORPTION OF CALCIUM & VIT.D
-INCREASE LEVELS OF IL-6 IL-1 AND TNF- 
-DECREASE IGF, TGF- SECRETION
-DECREASE CALCITONIN LEVELS
PATHOGENESIS OF BONE LOSS DUE
TO CALCIUM/VITAMIN D
DEFICIENCY IN THE AGED
Estrogen
deficiency
Impaired renal
function
Decreased calcium
absorption
Low dietary
Calcium intake
Decreased
vitamin D
synthesis
Secondary
hyperparathyroidism
Decreased sunlight
exposure
BONE LOSS
Why is osteoporosis such a
disaster to us?
5/23/2017
At least 1.5 million fractures occur each year as a
consequence of osteoporosis.
 There are about 700,000 vertebral crush
fractures per year in the
 About 300,000 hip fractures occur each year,
most of which require hospital admission and
surgical intervention.
 high incidence of deep vein thrombosis and
pulmonary embolism (20–50%) and a mortality
rate between 5 and 20% during the year after
surgery.

16
5/23/2017
Risk is equal to a combined risk of uterine, breast
and ovarian cancer
Mortality rate is 20%, and 50% never fully recover
17
CLINICAL MANIFESTATIONS
 Osteoporosis
5/23/2017
O NO CLINICAL MANIFESTATION UNTIL
THERE IS A FRACTURE
is a silent Thief
19
CLINICAL MANIFESTATIONS

Fracture (may be asymptomatic)

Vertebral fractures (T8-L3)

Colles' fracture of distal forearm

Hip fractures

Other sites
Back pain
Loss of height
Dowager’s hump (dorsal kyphosis, and cervical lordosis)
21
Vertebral Fracture Cascade
DIAGNOSTIC INVESTIGATION
DIAGNOSIS

Examination

Measurements of height, posture, gait,
strength, balance, and reflex testing
ASSESSMENT OF BONE DENSITY,
OSTEOPOROTIC RISK
Conventional radiography is an
insensitive technique for diagnosing bone loss
Demineralization or compression fractures
of vertebral bodies
Estimated 25% to 50% of bone mass must be lost
to show osteopenia on radiographs
Radiographic
Assessment
Radiographs may demonstrate signs of secondary osteoporosis
subperiosteal resorption in hyperparathyroidism
local sites of lytic destruction in malignancy
pseudofractures in osteomalacia
DEXA (gold standard):
dual-energy x-ray absorptiometry (DEXA) is both precise and safe,
with a low radiation exposure.
With reproducibility errors of approximately 0.6%
to 1.5%,
newer DEXA techniques measure bone
density rapidly, in 0.5 to 2.5 minutes.
Bone Mineral Density Compared with:
peak bone mass of young, healthy controls (T score)
age-matched controls ( Z score)
bone densitometry identifies patients with an increased
gradient of risk for fracture.
in women older than 65 years, hip bone density
is predictive of spine and hip fracture
1 SD decreased in BMD = 2 times increased in fracture risk
BMD measurement:
INDICATIONS FOR BONE DENSITOMETRY
Indications for Bone Densitometry
All postmenopausal women < 65 yr who have one or more
additional risk factors for osteoporosis (besides menopause)
All women > 65 yr regardless of additional risk factors
To document reduced bone density in patients with vertebral
abnormalities or osteopenia on radiographs
Estrogen-deficient women at risk for low bone density who are
considering use of estrogen or an alternative therapy
to monitor the efficacy of a therapeutic interventions for
osteoporosis(23 month)
To diagnose low bone mass in glucocorticoid-treated individuals
To document low bone density in patients with asymptomatic
primary or secondary hyperparathyroidism
Screening normal premenopausal women is not cost-effective
The World Health Organization criteria for osteoporosis:
1. Normal bone density if the T score is greater than −1
2. Osteopenia (low bone mass) is defined as T score between −1 and −2.5
3. Osteoporosis is defined as a bone density measurement less than 2.5 SD
below that of young, healthy controls (T score < 2.5)
The National Osteoporosis Foundation recommends treatment for all
individuals who have a lumbar spine, hip, or femoral neck T score of −2.5 or
lower.
bone density between −1 and −2.5 Performing a Fracture Risk Assessment
(FRAX)
FRAX provides a 10-year risk of a hip fractures or a major osteoporotic
fracture (proximal humerus, and wrist).
The clinical risk factors in the FRAX program: age, weight,
height, history of a fracture as an adult, parental history of
a hip fracture, current glucocorticoid use, secondary cause
of osteoporosis, alcohol intake and current smoker
Threshold to recommend treatment
10-year risk of: hip fracture ≥ 3% or major osteoporotic fracture ≥ 20%
it is important to enter the country in which you are practicing medicine.
Evaluation of Osteoporosis
Evaluation for Secondary Bone Loss
For All Patients
Laboratory tests including CBC, TSH, PTH, ESR
serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D levels,
measurement or estimate of 24-hr urinary calcium and creatinine levels
For Selected Patients
(Children, premenopausal women, men younger than 60 yr, patients with rapidly progressive
disease)
Definitive tests for endocrine, neoplastic, and gastrointestinal disorders
liver function tests,
Bone biopsy
markers of bone turnover
serum and urine protein electrophoresis for patients older than 50 years
In men, serum testosterone and luteinizing hormone
MANAGEMENT AND TREATMENT
Management of Osteoporosis
Lifestyle
Diet
Exercise
Smoking
Sunlight Exposure
Pharmacological
Drugs altering BMD
Analgesia
Non-pharmacological
Physiotherapy
Pain Relief
Falls Assessment
PAIN CONTROL IN FRACTURE

Oral analgesics are first-line therapy for the relief of acute pain due to vertebral
compression fractures.

For inadequate pain relief with oral analgesics, adding calcitonin

NOT using vertebroplasty or kyphoplasty for the acute management of pain
associated with osteoporotic compression fractures

NOT using skeletal muscle relaxants for the acute management of pain in patients
with osteoporotic compression fractures

If bracing is used to relieve pain, braces should be discarded as soon as possible,
since they promote immobility of the spine and the potential for disuse osteoporosis
ADEQUATE INTAKE OF CALCIUM &VIT D
 The
NOF :
women age 51 & older :


men age 50-70 :


1,200 mg per day of calcium.
1,000 mg per day of calcium
men age 71 and older :

1,200 mg per day of calcium.
INTAKE OF CALCIUM

excess of 1,200 to 1,500 mg per day :

may increase the risk of developing
kidney stones
 cardiovascular disease
 stroke

ADEQUATE INTAKE OF
CALCIUM & VITAMIN D


Increasing dietary calcium is the first-line approach,
but calcium supplements should be used when an
adequate dietary intake cannot be achieved
A balanced diet rich in low-fat dairy products, fruits
and vegetables provide calcium
WHO NEED CALCIUM PILL
SUPPLEMENTATION

Patient treated for osteoporosis

Patient treated with gluococorticoids

Individuals with low calcium intake
CALCIUM
 Carbonate with meals & need acid for absorption
 Calcium citrate don’t need acid & don’t produce renal
stones
 Night is good time for calcium supplementation
 If over 500 mg must used divided dose especially
breakfast
 Calcium supplementation reduce iron absorption by 50%
Vitamin D plays a major role:
 In calcium absorption
bone health
•400 IU daily
•Vitamin D is in milk
(100 IU in 1 cup)
ADEQUATE INTAKE OF VITAMIN D
Vitamin D supplements should be
recommended in amounts sufficient
to bring the serum 25(OH)D level to
approximately 30 ng/ml

FALL PREVENTION
90% of all non vertebral fractures are related to fall

Correction of decreased visual acuity

Reduction of drug consumption that altered wakefulness &
balance

Improve cardiac & neurologic function

Improve muscle strength

Improving home environment

Wearing hip protectors
Pharmachologic Therapy
Current treatments in OP

–

Antiresorptive
 Estrogens and SERMs
 Calcitonin
 Bisphosphonates
 Denosumab
Anabolic (stimulate bone
formation)
 Parathyroid hormone
Dual action agents
 Strontium ranelate
Osteoclast
Inhibition of
resorption
Osteoblast
Stimulation of
formation
Hormone replacement therapy
 Estrogen therapy decreased the risk of hip
fractures by 25% to 30% and the risk of
vertebral fractures by 50%.
HORMONE
REPLACEMENT THERAPY
Increased risk of
seven more cardiac events,
eight more breast cancer ,
eight more stroke,
eight more pulmonary emboli,
six fewer colorectal cancers,
five fewer hip FX
•
TESTOSTERONE
•
Men with hypogonadism may benefit from
TES replacement therapy
Selective estrogen
receptor modulators
 Raloxifene (Evista): Increased BMD,
decreased risk of vertebral fractures (but
not non-vertebral), LDL, risk of invasive
breast cancer
 Dose: 60 mg/day
 Adverse effect: Hot flushes, DVT
SELECTIVE ESTROGEN RECEPTOR MODULATOR

SERMs are not recommended for premenopausal women.
CALCITONIN

A less popular choice for treatment of osteoporosis is
nasal spray
 200 units (1 spray) daily

IM/SQ
 100 units/every other day
 Should perform skin test prior to initiating
therapy
CALCITONIN

We prefer other drugs to calcitonin
Weak anti-fracture efficacy compared with
bisphosphonates & parathyroid hormone
 No
significant effect in the hip region
Bisphosphonates

Alendronate (Fosamax)

Risedronate (Actonel) better GI profile

Ibandronate (Boniva) no hip protection

Zoledronic Acid (Aclasta) once a year
Bisphosphonates
• Alendronate: 70 mg weekly for treatment, 35 mg weekly
for prevention
• Risedronate: 5 mg daily or 35 mg weekly (tablet); 150 mg
monthly (tablet)
• Ibandronate: 150 mg monthly by tablet; 3 mg intravenously
over 15 to 30 seconds every 3 months
• Zoledronic acid: 5 mg by intravenous infusion over a
minimum of 15 minutes once every year
*
BISPHOSPHONATES: INDICATIONS

Treatment and prevention of postmenopausal
osteoporosis

Prevention and/or treatment of glucocorticoidinduced osteoporosis

Treatment of men with low bone density
Bisphosphonates
– Tablets taken on an empty stomach after overnight
fast with plain water while in an upright position
– Patients should not eat or lie down for at least 30
minutesnate
– Calcium and vitamin D supplements, if needed,
should be taken at a different time of day
BISPHOSPHONATE HOLIDAYS
 In
patients at high risk for fractures (previous
fractures, older age, high risk for fall, etc), continued
treatment seems reasonable. Consider a drug holiday
of 1 to 2 years after 10 years of treatment.
lower risk patients, consider a “drug holiday”
after 4 to 5 years of stability.
 For
Bisphosphonates
Side effects:
 Heart burn, Reflux,Esophagitis, Ulcer
 Artheralgia, myalgeia
 Flu-like symptoms
 Hypocalcemia
 Atrial fibrillation (2%)
 Osteonecrosis of Jaw: more common with potent (
Zoledronic acid), 1/10,000 to 1/100,000
Risk factors: Chemotherapy, Steroids,
Dental extraction, and periodontal disease
 Subtrochanteric fractures: Prevalence?
Rate higher in alendronate users
TERIPARATIDE (CINNOPAR)
The only treatment agent that:
stimulates bone formation
• 20 μg daily (subcutaneously) for no more than 2
years
• Forteo® prefilled pen contains 28 daily doses
Befor TX
After Tx
DENOSUMAB

Denosumab is a humanized monoclonal antibody against
RANKL that reduces osteoclastogenesis.
RANK Ligand Is an Essential Mediator of
Osteoclast Activity
IL-11
TNF-
Many different factors can
affect osteoclast activity, but
most do so through the
osteoblast and RANK ligand
(RANKL)
IL-1
PTH
Vitamin D
RANKL
PGE2
Osteoblast
PTHrP
Glucocorticoids
Osteoclast
TNF-=tumor necrosis factor-alpha; PTHrP=parathyroid hormone-related
peptide; PTH=parathyroid hormone; IL-1, IL-11=interleukins-1, and -11;
PGE2=prostaglandin E2.
Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.
Hofbauer LC, et al. JAMA. 2004;292:490-495.
© 2009 Amgen. All rights reserved.
5
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educationalresource.
resource.Do
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notcopy
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distribute.
Provided
DENOSUMAB (PROLIA®)
60 MG SUBCUTANEOUS INJECTION EVERY 6 MONTHS

Denosumab is approved by the FDA for
 Treatment of osteoporosis in postmenopausal
women at high risk of fracture
 To increase bone mass in men
 Treat bone loss in women with breast cancer
 To treat bone loss in men receiving certain
treatments for prostate cancer
 Used in renal failure
OTHER THERAPIES
•
Calcitriol : Effective in preventing glucocorticoidinduced and posttransplant-related bone loss
Strontium ranelate (Protelos)
 Vitamin K
 Tibolone
 Folate/vitamin B12
 Growth factors
 Androgens
 Isoflavones
 Fluoride

Choice of therapy
o The bisphosphanates should remain first
o
o
o
o
line agents
First: alendronate or Risedronate, if
intolerance: Zoledronic or Ibandronate
Raloxifen, Calcitonin, and PTH should
remain second line agents
PTH may be an option for women who
have failed other treatment
Denosumab FDA approved for woman
with breast cancer and for
posmenopauseal women with
osteoporosis, renal failure
‫‪MANY THANKS‬‬
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