Transcript Slide 1

Osteoporosis and Bone Mineral
Density
Netee Papneja
PGY4 Endocrinology
Objectives
To review the basic of Osteoporosis:
definition, epidemiology, and risk factors
 To review the current Osteoporosis
guidelines for women and men
 To review basics of BMD and it's
interpretation

What is Osteoporosis?

A skeletal disorder - compromised bone
strength (low bone mass and poor quality) =
increased risk for fragility fracture
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Fragility fracture: occurs spontaneously or with
low trauma from standing height or less
Osteoporosis
◦ Fragility # represent 80% of all fractures in menopausal
women > 50
◦ 1-year mortality after hip fracture ranges 8.6% to 36%
and only 25% return to baseline functioning

Large care gap exists
◦ <20% of women receive therapies to reduce future
fracture within the year following fracture and <10% of
men!
◦ 60% of women with fragility fractures have
non-osteoporotic bone mineral density
(T-score >-2.5)
Bessette L et al. The care gap in diagnosis and treatment o f women with a fragility fracture. Osteoporos Int
2008;19:79-86.
Abrahamsen B et al. Excess mortality following hip fracture: a systematic epidemiological review. Osteoporos Int
2011;20:1633-50.
Pathogenesis
◦ Low peak bone mass
 Consequence of peak bone mass accrued in utero
and during childhood and puberty
 Genetic factors account for up to 85% of peak
bone mass determinant
 Other influences: hormonal, nutritional, and
environmental
◦ Increased bone re absorption (ex. Low
Estrogen)
◦ Decreased bone formation (ex. Steroids)
Secondary Osteoporosis

Secondary osteoporosis (20% in women
and 50% cause in men):
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Genetic
Hypogonadism
Endocrine
Nutritional and GI related
Hematologic and neoplastic
Medication Induced
Miscellaneous
Endocrine Causes
Disorders strongly associated with
osteoporosis include:

Endocrine:
◦ Primary hyperparathyroidism, Type I diabetes,
Osteogenesis imperfecta in adults, Untreated
long-standing hyperthyroidism, hypogonadism,
Cushing’s disease
menopause (<45 years)
 Chronic malnutrition or malabsorption
 Chronic liver disease
 Chronic inflammatory conditions

How is the diagnosis of
Osteoporosis Made?
Can be made or suspected if + fragility #
 In pre-fracture patient, the WHO
recommends making the diagnosis based
on BMD value at lowest skeletal site:

 NORMAL: T- score over -1
 OSTEOPENIA (Now replaced by LOW
BONE MASS): T-score -1 TO -2.5
 OSTEOPOROSIS: T-score over-2.5
BMD basics
Measures bone mass to establish
diagnosis of osteoporosis, predict risk of
subsequent fractures and to monitor
changes in BMD during therapy
 Methods of measuring BMD:

◦ Dual energy x-ray absorptiometry (DXA)
◦ Quantitative ultrasonography (QUS)
◦ Quantitative computed tomography (QCT)
How does bone densitometry
measure bone mass?
Technique uses an ionizing radiation
source (from a radionuclide or from xrays) and a radiation detector to measure
amount of calcium in bone.
 Principle: bone will absorb radiation in
proportion to it’s bone mineral content
 Bone mineral content then divided by
measured area
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Dual energy x-ray absorptiometry
(DXA)
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Preferred method of measuring bone
mass
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DXA measures bone mineral content
(BMC, in grams) and bone area (BA, cm2)
◦ "areal" BMD (aBMD) is calculated in g/cm2 by
dividing BMC by BA
Bone Mineral Density: DXA
Patient on whole body scanner, with x-ray sources beneath a
table and a detector overhead. Scanned with photons that are
generated by 2 low-dose x-rays at different energy levels. The
body's absorption of the photons at the two levels is
measured. The ratios can be then used to predict total body
fat, fat-free mass, and total body bone mineral.
Advantages of DXA Scans

precise, accurate, and reliable
PRECISION ERROR
(%)
ACCURACY ERROR
(%)
RADIATION DOSE
(mSV)
Spine
1
5-8
1
Proximal femur
1-2
5-8
1
Total body
1
1-2
3
• Relatively short scanning times (few minutes)
• low radiation exposure
• DXA can also distinguish regional as well as whole
body parameters of body composition.
Disadvantages
◦ Initial cost of the equipment
◦ Significant differences in the technologies
used by different manufacturers
 Same centre
 Same machine and calibration
 Same technician
◦ Contraindicated in pregnancy
◦ Careful of falsely low or high results
Factors modifying bone
mineral density
INCREASED BMD
DECREASED BMD
HIP
Excessive or inadequate internal hip rotation
rotation
Osteoarthritis
Metal artifact
Focal skeletal sclerosis
Artifact overlying soft
tissue
Lytic lesions
SPINE
Osteophytes
Focal skeletal pathology (i.e., sclerosis,
metastasis)
Vertebral compression #
Vascular calcification
Metal, radiology contrast, stones, calcium
tablets or other artifact overlying spine
Artifacts overlying soft
tissues
Rotoscoliosis
Laminectomy
Lytic lesions
CARJ Vol 56, No 3, June 2005 179
What do results mean?
What is a T score?

Number of standard deviations above or below the mean
bone mass of a normal young adult sex-match
population
◦ A patient whose bone mass is 1 SD below that of the
reference population has a T-score of -1.0 and has lost
about 10% of bone mass
What is a Z score?

# of SD above/below the mean bone mass of an age- and
sex- matched reference population
Best bone to use?
Hip is preferred because bone mass at hip
site best correlates with risk of hip
fractures (highest mortality and
morbidity)
 Role of forearm bone mass?
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◦ Useful in primary hyperparathyroidism, if
patient overweight and cannot be scanned
Main Focus….
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Manage the patient according to their
absolute fracture risk and not their BMD
◦ 60% of women with fragility fractures have
non-osteoporotic bone mineral density
(T-score >-2.5)
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Over-reliance on BMD: missed
opportunity to prevent future fractures
Screening
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Individuals over the age of 50
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Anyone with a history of fragility fracture
• A detailed history and physical exam can help
identify individuals at high risk of fractures
How do I assess for
osteoporosis and fracture risk?
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History – identify RF for low BMD, future
#, falls
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History of fracture
Parental hip fracture
Steriod use (>3months, 7.5mg)
Smoker
High alcohol intake (>3units/day)
Inflammatory disorders (ie RA)
Falls in last 1 year
Gait and balance issues
Screening Examination
Parameter
Weight
Under 60 kg
Weight loss ≥ 10% since age 25
Height
(measure
annually)
Vertebral
fracture
assessment*
Positive Results
Prospective loss > 2 cm
Historical height loss > 6 cm
Rib-to-pelvis
distance
≤ 2 fingers’ breadth
Occiput-towall distance
(kyphosis)
> 5 cm
Fall risk assessment:
Get-up-and-go test
Inability or difficulty performing test
Long time (> 30 seconds) to
complete2
*If vertebral fracture assessment is
positive, screen for vertebral fracture
using lateral spine x-ray
1. Papaioannou A, et al CMAJ 2010.
JAMA
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Does this woman have osteoporosis?
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Weight < 51 kg LR+7.3
Tooth count <20 LR+ 3.4
Self-reported humpback LR +3.0
Rib Pelvis < 2 finger breadth LR+3.8
Wall to Occiput >0cm LR+4.6
Next Steps… BMD
BMD for:
1. >65
2. Presence of fracture
3. Individuals who have risk factors
Osteoporosis: Investigations
•
Recommended tests for for people with
osteoporosis, defined as T-score ≤ -2.5:
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Calcium, corrected for albumin
Complete blood count
Creatinine
Alkaline phosphatase
Thyroid-stimulating hormone
Serum protein electrophoresis (for patients with
vertebral fractures)
◦ 25-Hydroxyvitamin D
Osteoporosis: Risk Assessment
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Two tools available:
◦ Canadian Association of Radiologists and
Osteoporosis Canada (CAROC)
◦ Fracture Risk Assessment tool (FRAX)
Osteoporosis: Risk Assessment
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CAROC
◦ Uses age, sex, and femoral neck T-score
◦ 10-year risk of major osteoporotic fracture is
determined
◦ 2 Risk factors raise a patient’s risk level
to next category
 Fragility fracture after age 40
 Prolonged systemic glucocorticoid use
Osteoporosis: CAROC
Osteoporosis: CAROC
Osteoporosis: Risk Assessment
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FRAX
◦ Developed and recommended by the WHO
◦ Uses sex, age, femoral neck T-score (optionally),
and:
BMI
Prior fracture
Parental hip fracture
Prolonged glucocorticoid use
Rheumatoid arthritis (or secondary cause of
osteoporosis)
 Current smoking
 Alcohol intake >3/d
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◦ 10-year probability of major osteoporotic
fracture and hip fracture is calculated as a %
FRAX Tool: On-line Calculator
www.shef.ac.uk/FRAX.
CAROC Verses FRAX
Both reflect risk assessment in treatment-naïve
patients
 FRAX more complete, but complex to use, not
available in BMD machines
 The CAROC tool is the only tool that can be applied
nationally at the present time.
 2010 CAROC tool is recommended for use in
Canada by Osteoporosis Canada; it is also available in
an electronic format.
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Treatment- Non pharmacological
For ALL Patients
1. Exercise – Resistance, weight-bearing
aerobic exercises, that enhance core
stability and/or focus on balance (i.e.
tai chi)
2. Hip protectors for LTC residents
3. Smoking cessation
4. Reduce alcohol
5. Fall-prevention strategies
Osteoporosis: Calcium & Vit D
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New Osteoporosis Canada Guidelines:
◦ Adults over age 50
 Total daily intake of elemental calcium (through diet
and supplements) should be 1200 mg
◦ Healthy adults at low risk for vitamin D deficiency
 Vit D3 400-1000 IU daily
◦ Adults over age 50 at moderate risk of vitamin D
deficiency
 Vit D3 800-1000 IU daily (up to 2000 IU may be
required)
Treatment
CAROC stratification guides treatment decisions
Women
0.0
Femoral neck T-score
-0.5
-1.0
Low risk (<10%)
-1.5
-2.0
Moderate risk
(10-20%)
-2.5
-3.0
-3.5
High risk (> 20%)
-4.0
50
55
60
65
70
75
80
85
Age (years)
Papaioannou A, et al CMAJ 2010.
Pharmacological Treatment
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Low risk (10-year risk <10%)
◦ Treatment not recommended. Reassess risk in 5
years
Moderate risk (10-year risk 10-20%)
◦ Consider treatment if additional risk factors or
vertebral # present
High risk (10-year risk >20%)
◦ Should be offered pharmacologic therapy
Factors to Consider in moderate risk patients
Fracture
• vertebral fracture
• Previous wrist fracture in individuals either > 65yrs or
with a T-score ≤-2.5
BMD
• Lumbar spine T-score << femoral neck T-score
• Rapid bone loss
Medications
• Aromatase-inhibitor or androgen deprivation therapy
• Long-term or repeated systemic glucocorticoid use not
meeting conventional criteria for prolonged use
Other
• Recurrent falls (≥ 2 times in the past 12 months)
• Disorders strongly associated with osteoporosis, rapid
bone loss or fractures
First-line therapies in post-menopausal women
Based on GRADE A evidence
Bone
Formation
Therapy
Antiresorptive Therapy
Type of
Fracture
Bisphosphonates
Denosumab
(Prolia)
RANK
ligand
Inhibitor
SERM
Raloxifene
*
Estrogen
**
(Hormone
Therapy)
Teriparatide
(Forteo)
PTH analog
Alendronate
Risedronate
Zoledronic
Acid
Vertebral
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Hip
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-
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-
Nonvertebral†
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-
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*For
menopausal women can be used as a first-line for
prevention of vertebral fractures
**For menopausal women with vasomotor symptoms
Papaioannou A, et al CMAJ 2010.
Papaioannou A, Morin S. CMAJ. 2010.DOI:10.1503/cmaj.100771.
Osteoporosis: Treatment

Osteoporosis Canada Guidelines for
Menopausal women:
Second line therapy: calcitonin or etidronate for
prevention of vertebral fractures [grade B]
Treatment: Bisphosphonates
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Osteonecrosis of the jaw (ONJ) 1/100,000 pts/
yr
◦ nonhealing area of exposed bone in the jaw
◦ Commonly after dental procedures
◦ Mostly with higher doses of IV BP use for cancer, in
patients with co-factors like chemo, radiation, steroids
Atypical Fracture: subtrochanteric or shaft
fracture
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2/100,000 pts on 2yrs BP
78/100,000 pts on 8yrs BP
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Treatment: RANKL antibody
60mg SC q6months
 Denosumab (Prolia) is a monoclonal antibody
against Rank Ligand
◦ Inhibits Rank Ligand, a protein which activates
osteoclasts. Denosumab blocks osteoclast
differentiation and reduces osteoclast numbers and
thereby inhibiting bone reabsorption.
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Long-term safety data not available
Not studied in men
Used in:
◦ Patients who have failed, are intolerant of other
therapies, poor adherence, patient preference
◦ Covered by OBD if 2/3 present: >75, BMD <-2.5,
fracture
Cummings SR et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J
Med. 2009;361(8):756
Treatment: Recombinant PTH
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FORTEO® (teriparatide [rDNA origin]
injection) 20 microgram SC OD x 2years
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$800/month
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Vertebral and Non Vertebral # prevention
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Consider using in:
◦ Men and women with severe osteoporosis who
continue to fracture after bisphosphonate
therapy
◦ Intolerance to bisphosphonates
SERM
Selective estrogen receptor modulatorRaloxifene (Evista)
 Reduces only vertebral fractures
 Breast Ca protection/no endometrial
hyperplasia
 Increases risk of venous
thromboembolism/hot flashes

HRT
reduce overall fractures with a relative
risk reduction of 30%
 Risks associated with VTE, stroke and
Breast Cancer
 Requires assessment of risks, benefits and
patient preference
 Consider with intolerable menopausal
symptoms
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Treatment: Calcitonin
Binds to osteoclasts and inhibits bone
reabsorption
 Can be given IM, SC, or intranasal
 Less efficacious than other therapies
 Reduces only vertebral #
 Can be considered in patients with back
pain
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Duration of Bisphosphoates (BP) Treatment
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Large, RCTs show benefit of BP therapy for 3-4 yrs
Only two RCT looking at use of BP beyond 5 years
◦ Fracture Intervention Trial Long-Term
Extension (FLEX)- 1099 postmenopausal women on
avg 5yrs of Alendronate to continue it or placebo for
additional 5 yrs
◦ Health Outcomes and Reduced Incidence with
Zoledronic Acid Once Yearly (HORIZON)
Extension trial- 3 years of treatment followed by 3
years of active extension (n = 616) or placebo ( n =
617)
n engl j med 366;22 nejm.org may 31, 2012

FLEX and HORIZON trials:
◦ modest bone loss after D/C of therapy as
compared to continued therapy ?persistent effect
of alendronate (5 years) and zoledronic acid (3
years)
◦ Both showed significant reductions in the risk of
vertebral # with continuation of bisphosphonate
treatment
◦ Neither trial showed an overall reduction in
nonvertebral fractures.
n engl j med 366;22 nejm.org may 31, 2012
5-Yr Risk of Clinical Vertebral Fracture
FN T score
at start
Placebo
Alendronat
e
Risk
Difference
NNT
ALL BMD
23/437 (5.5)
16/662 (2.5)
2.9 (0.3–5.4)
34
<-2.5
-2.5 to -2
>-2
11/132 (9.3)
9/126 (5.8)
3/179 (2.3)
9/190 (4.5)
3/185 (2.8)
4/282 (1.1)
4.8 (0.8–9.2)
3.0 (0.3–6.7)
1.2 (0.2–2.8)
21
33
81
6/75 (8.0)
3/82 (3.0)
2/130 (1.8)
4/109 (3.8)
1/121 (1.4)
2/203 (0.9)
4.2 (0.6–9.1)
1.6 (0.2–5.0)
1.0 (0.1–2.6)
24
63
102
No
Vertebral #
<-2.5
-2.5 to -2
>-2
Vertebral #
<-2.5
Continuing
for Osteoporosis
5/57 Bisphosphonates
(11.1)
5/81 (5.3)
5.8 (0.8–
17
Osteoporosis: Treatment

Monitoring:
◦ Treatment initiation: 1-3 years after
 Good response if BMD improves or stabilizes
 Poor response: Decrease in BMD greater than the least
significant change (LSC) of the measuring facility
 adherence issues, undiagnosed secondary causes
◦ Moderate risk: repeat BMD testing in 1-3 years to
assess for rapid decline in BMD
◦ Low risk individuals: repeat at 5-10 year interval
Bone Turnover Markers (BMT)
Prospective studies: increased levels of BTMs are
associated with ~ two-fold increased # risk in
women 65 and older
 In estimating the 10- year absolute risk of hip
fracture, the combination of an elevated
reabsorption marker (C-terminal telopeptide) with
an osteoporotic BMD or a history of previous
fracture resulted in a 70-100% higher risk than from
BMD alone
 The value of BTMs still unclear, not integrated in any
fracture risk assessment system.

Monitoring: Cross-linked
C-terminal telopeptides (CTX)
proteolytic fragments of type 1 collagen
formed during bone resorption
 high levels of CTX = higher rate of bone
remodeling (turnover)
 Menopause = Low estrogen = reduced
osteoblasts and thus accelerating the rate
of bone loss: higher CTX
 antiresorptive therapy: CTX back to premenopausal level
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Interpretation:
◦ drop in CTX concentration of 35 to 55 percent from
baseline levels after three to six months indicates
effective antiresorptive therapy.
◦ Ineffective therapy or lack of compliance = absence of
a decline
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Provides early indication of treatment response
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Changes in bone turnover can be detected in
three months by measuring CTX
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testing for CTX is noninvasive and can be
repeated often.
Limitations
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variability of CTX due to diet, exercise, time of
day, etc
cannot replace BMD in diagnosing osteoporosis
Although levels of CTX are associated with
increased risk of fractures, the test cannot be
used to predict fractures.
Low GFR: CTX concentrations may be higher
than expected due to reduced excretion of CTX
Treatment
Osteoporosis Guidelines for Men
2012

Evaluation with BMD
◦ >70
◦ 50-69 yo if additional RF (ex. fragility #,
steroids, hypogonadism, hyperparathyroidism,
or COPD)

Hyperparathyroidism or anti-androgen tx
for prostate ca: measure forearm dXa
(1/3 or 33% radius)
Treatment- Lifestyle
1000–1200 mg calcium daily
 Obtain vitamin d levels > 75 nmol/liter
 weight-bearing activities for 30–40 min
per session, 3-4/wk
 Etoh <3/day
 cease smoking
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Pharmacological
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Treatment for:
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hip or vertebral fragility fracture
BMD below -2.5 at any site
>20% 10yr risk of fracture
Long term steroids
Options
◦ alendronate, risedronate, zoledronic acid, and
Forteo; also Prolia for men receiving adT for
prostate cancer
Special Groups

hypogonadal men
◦ High risk: Testosterone + bisphosphonate or
Forteo
◦ Borderline high risk: Testosterone if it’s
<6.9nmol/L and positive signs of symptoms
low androgen or chronic hypogonadism (due
to HPA problem)

Men with prostate cancer receiving ADT
◦ High risk: Recommend pharmacological
treatment of OP
Monitoring
BMD q1-2 years until plateau reached,
then reduce frequency
 consider measuring a bone turnover
marker (CTX) at 3–6 months after
initiation for anabolic therapy (Forteo)

Summary
Osteoporosis is prevalent and causes a
great burden by increasing fractures
 Assessment of osteoporosis should
include determination of risk factors and
BMD
 Two validated tools (CAROC and FRAX)
are available for fracture risk assessment
in Canada
 Pharmacologic treatment is guided by risk
level

Thank you!
Special thanks to Dr. Paul and Ronen